Comparative Overall Survival of Breast Conservation Therapy and Mastectomy in Young Women with Breast Cancer: A Comprehensive Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-4919484/v1

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Systematic Review

Comparative Overall Survival of Breast Conservation Therapy and Mastectomy in Young Women with Breast Cancer: A Comprehensive Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-4919484/v1

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Young age is recognized as an independent risk factor for local recurrence following breast-conserving therapy (BCT) and whole-breast radiotherapy (WBRT) for patients with breast cancer. The objective of this meta-analysis was to evaluate and compare the 5-year and 10-year overall survival (OS) rates between patients who underwent BCT and those who underwent mastectomy for the treatment of breast cancer. The analysis is meticulously stratified by tumor stage (T1, T1-2, T1-3) and lymph node stage (N0-1, N0-3) to offer a more detailed understanding of the long-term outcomes associated with these two surgical interventions.

Materials and Methods: Our review included 8 studies that compared OS between BCT and mastectomy in young patients (< 40 years) diagnosed with stage I-IV breast cancer. The endpoint was OS, and only studies presenting fully adjusted hazard ratios (HRs) were included in the analysis. Summary odds ratios (ORs) were calculated via random effects models. We assessed publication bias and heterogeneity through sensitivity analyses and meta-regression models.

Results: Eight population-based studies encompassing a total of 49,285 patients aged 40 years or younger were included: 23,280 patients received BCT, while 26,005 underwent mastectomy. For the 5-year OS, the combined effect size OR was 1.45 [0.89, 2.37], which was not statistically significant. For the 10-year OS, the OR was 1.30 [1.00, 1.69], which was statistically significant and was accompanied by notable heterogeneity (I² = 95.1%). The overall effect size, which combines both follow-up durations, was OR = 1.33 [1.07, 1.65], indicating a superior OS for patients who underwent BCT compared with mastectomy, albeit with considerable heterogeneity (I² = 94.2%, p = 0.000). In the forest plot analysis by tumor stage, for T1 tumors, the combined effect size OR was 1.49 [1.23, 1.80], with no significant heterogeneity (I2 = 0.0%). Tumor Stage T1-2: Combined effect size OR = 1.09 [0.84, 1.34], with significant heterogeneity (I2 = 92.7%). Tumor Stage T1-3: Combined effect size OR = 1.73 [0.92, 3.25], with significant heterogeneity (I2 = 95.7%). Forest plot analysis by lymph node stage: The combined effect size OR = 1.19 [0.99, 1.44], with significant heterogeneity (I2 = 91.1%). Lymph node stage N0–3: Combined effect size OR = 1.73 [0.92, 3.25], with significant heterogeneity (I2 = 95.7%). The OS of the T1 subgroup in the BCT group was significantly greater than that in the mastectomy group, whereas the difference in OS among the other subgroups was not statistically significant. Leave-One-Out Sensitivity Analysis: The leave-one-out sensitivity analysis demonstrated that the overall odds ratio remained robust, indicating that the results were not disproportionately swayed by any single study. This analysis ensures the reliability and consistency of the findings across the included studies. Meta-regression analysis: To delve into the potential sources of heterogeneity, a meta-regression analysis was conducted, scrutinizing study-level covariates, including 'Nstage' (node stage) and 'Tstage' (tumor stage). The findings are as follows: 'Nstage': the coefficient is -0.1317, with a p value of 0.844, which implies that there is no significant effect on the magnitude of the outcome. 'Tstage': The coefficient is 0.2857, with a p value of 0.512, also indicating that there is no significant influence on the effect size. Egger’s test for publication bias: The outcomes of Egger’s test for publication bias are as follows: Beta1 = -2.20, standard error (SE) = 1.172, z score = -1.88, p value = 0.0599. The p value hovers near the threshold for significance, hinting at a marginal suggestion of small-study effects. However, it does not provide definitive evidence of publication bias, thus maintaining the integrity of the reported results.

Conclusion: The combined effect size from both follow-up periods had an OR of 1.33 [1.07, 1.65], which signifies a noteworthy 33% reduction in risk for BCT compared with mastectomy. These findings suggest that patients who undergo BCT experience superior overall survival, particularly in terms of 10-year overall survival. Subgroup Analysis for T1 Stage: The data suggest that BCT may confer a higher overall survival rate, with an OR of 1.49 [95% CI: 1.23–1.80]. The I2 statistic of 0 indicates the absence of heterogeneity, implying that patients receiving BCT demonstrate a 49% enhancement in overall survival compared with those undergoing mastectomy. Leave-one-out sensitivity analysis indicated that the results are not unduly influenced by any single study, thereby reinforcing the reliability of the findings. Meta-regression analysis indicated that neither the nodal stage (N stage) nor the tumor stage (T stage) significantly affected the effect size. Egger’s test shows that the findings remain robust and free from the influence of potential publication biases.

Epidemiology

breast cancer

breast-conserving therapy

mastectomy

overall survival

BCT combined with WBRT is considered the primary surgical treatment option for patients with early-stage breast cancer, as it offers survival benefits equivalent to those of mastectomy across various age groups.^[1] The European Society of Breast Cancer Specialists (EUSOMA) working group has endorsed BCT followed by radiation therapy as the preferred approach whenever appropriate for young women diagnosed with breast cancer. This recommendation aligns with the consensus reached at the inaugural international conference focused on breast cancer in young women, and the 2013 St. Gallen Consensus Panel also concurred that being young is not an absolute contraindication for breast-conserving surgery. However, young patients with breast cancer constitute a distinct demographic group characterized by unique personal and clinical challenges, such as a predisposition to more aggressive tumor types, which can lead to a poorer prognosis. The selection of BCT as a local treatment modality for young women with early-stage breast cancer remains a contentious issue. Research has indicated that both BCT and mastectomy yield comparable survival benefits for this patient population. ^{[2, 3]} Nevertheless, in recent years, several studies have suggested that patients who undergo BCT may experience superior outcomes compared with those who opt for mastectomy. ^{[4, 5]} This could be attributed to advancements in radiotherapy and systemic treatments. However, the applicability of these findings to young individuals, who often present with more aggressive disease characteristics and a heightened risk of local recurrence,^[6] remains a subject of debate. Young patients are typically underrepresented in clinical trials, and to date, no randomized trials have been conducted to evaluate overall survival on the basis of the type of surgery in this age group.

Consequently, we conducted an extensive meta-analysis to address the critical question of whether BCT is as efficacious as mastectomy in terms of OS for patients under the age of 40 years who are diagnosed with breast cancer. Subgroup analyses were performed to compare the OS of patients with different stages of breast cancer who underwent the two surgical procedures.

Literature search

This review was conducted in strict accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The objective of this systematic review and meta-analysis was to report the OS outcomes for patients aged 40 years or younger with breast cancer who underwent either BCT or mastectomy. A thorough literature search was conducted by two reviewers, XiaoWen Ma and Qi Guo, using the following databases with established search strategies: PubMed, Medline, Cochrane, and Web of Science. The search was unrestricted by language or publication date, covering the period from January 1, 2004, to January 1, 2024. The search employed the following medical subject headings (MeSH): "breast cancer," "breast conservative surgery," "mastectomy," and "breast cancer in young women." All identified citations were independently assessed by the two authors and categorized as relevant or irrelevant. Studies deemed relevant were then selected for full-text review, and their reference lists were meticulously searched for additional significant citations. Ecological studies, case reports, reviews, and editorials were deemed ineligible for inclusion.

Eligibility criteria: Studies were included in the meta-analysis if they met the following criteria: 1. They published comprehensive adjusted risk estimates (at least accounting for age, tumor size, and lymph node status) comparing BCT with mastectomy in patients aged 40 years or younger with breast cancer, without any prior history of cancer or metastatic disease. 2. They were independent studies that did not duplicate results already published in another article. 3. The studies reported hazard ratios (HRs) or relative risks (RRs) for OS, along with their corresponding 95% confidence intervals (CIs).

We excluded studies that lacked a comparative group. Data extraction was performed with precision and independence by two reviewers, XiaoWen Ma and Qi Guo, ensuring consensus on all outcomes. A standardized data-collection protocol was meticulously applied to compile pertinent data from each article that was selected for inclusion. For each eligible study, we meticulously documented the following details: the lead author's name, the publication year, and a comprehensive set of study characteristics, including the research objective, the timeframe of patient recruitment, the geographical context of the study (whether it was conducted at a single center or based on a population registry), the eligibility criteria, the median follow-up period, the stage of breast cancer, the types of statistical adjustments made, the median age of the patient cohort, and the 5-year or 10-year OS rates.

Additionally, we recorded detailed information for each arm of the treatment groups, encompassing the total number of patients in the BCT and mastectomy cohorts, as well as the distribution of patients across various tumor stages (T1, T2, T3, T4, and TX), nodal stages (N0, N1, N2, N3, and NX), and the specifics of adjuvant treatments administered. This rigorous approach to data extraction and documentation ensured the integrity and reliability of the information used in our systematic review and meta-analysis.

Data analysis and statistical methods:

Our analytical approach was methodically organized into four principal steps:

We employed forest plot visualization to depict individual study estimates and the cumulative effect, followed by subgroup analyses stratified by tumor stage and lymph node status.
A leave-one-out sensitivity analysis was conducted to appraise the impact of each study on the aggregate estimate.
Egger's test was utilized to scrutinize potential publication bias.
Meta-regression analysis was executed to investigate the effects of study-level covariates on the magnitude of the effect size.
A correlation heatmap was constructed for correlation analysis to delineate the influence of various factors on OS and to gauge the robustness of the findings.

Each HR, meticulously adjusted for the most comprehensive array of confounding variables, along with their corresponding confidence intervals, was extracted and converted into an OR. The summary OR was computed by amalgamating the study-specific estimates through random effects models. The uniformity of effects across the studies was appraised via the chi-square statistic on the basis of a large sample test. Heterogeneity was deemed statistically significant at a P value threshold of 0.10. Furthermore, the I² statistic was employed to gauge the extent of heterogeneity, interpreted as the proportion of total variation across multiple studies that can be ascribed to heterogeneity: higher I² values signify increased heterogeneity. An I² threshold below 50% is conventionally viewed as an acceptable degree of variability. Forest plots were constructed, encompassing both the study-specific and the SOR estimates.

To assess the potential impact of bias, we adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, recommended for observational epidemiologic studies. Guided by the STROBE checklist, meta-regression was employed to evaluate between-study heterogeneity and to assess the influence of diverse study characteristics. Both meta-regression and subgroup analyses were conducted to quantify and elucidate the sources of between-study heterogeneity.

Heterogeneity and sensitivity analyses were meticulously evaluated, taking into account all conceivable factors that could sway the estimates, including adjustments for confounding factors, types of endpoints, and attributes of study designs. Publication bias was graphically appraised via Egger's test. All the statistical analyses were meticulously performed via Stata software version 17 and IBM SPSS Statistics 29.

Results of the Search Strategy:

In total, 1,398 articles were identified through the use of the specified MeSH terms. After an initial screening, 1,164 records were excluded on the basis of the abstract, leaving 234 articles that were deemed relevant for full-text review. We successfully retrieved and meticulously examined copies of all 18 eligible studies. Ultimately, 10 articles were excluded from the analysis: 1) Due to the utilization of an alternative endpoint definition^[7], the remaining 9 studies were omitted because they did not provide a direct comparison between BCT and mastectomy with respect to overall survival.

Description of studies

The characteristics of the studies included in the meta-analysis are delineated in Table 1. This table presents comprehensive details, including the total number of cases, publication year, country and diagnostic period, study design, age and tumor stage considerations, and duration of follow-up for each included study. Among the 8 population-based studies, a cumulative total of 49,285 patients aged 40 years or younger were included in the analysis: 23,280 patients who received breast-conserving surgery (BCS) and 26,005 patients who underwent mastectomy. ^{[5, 8–14]} All eight studies included patients who received treatment between 1988 and 2016.

The distributions of T stage and N stage for the two patient groups across these studies are illustrated in Table 2. Three articles included patients with tumors ranging from stage T1 to T4^{[7, 9, 10]}, three other articles focused on patients with tumors ranging from T1 to T2^{[5, 11, 13]}, and the remaining two articles specifically addressed patients with T1-sized tumors. ^{[12, 14]} In terms of lymph node stage, three articles featured patients classified as N0–N2. ^[8–10] The lymph node status in the remaining articles was categorized as N0–N1^{[5, 11–14]}. The cohort of patients who underwent mastectomy presented a greater prevalence of tumors larger than 2 cm, as reported in six studies^{[8–12, 14],} and a greater proportion of positive axillary lymph nodes, which was evident in seven studies^{[5, 8, 10–14]}. Notably, one study did not provide data regarding axillary lymph node status ^[9]. This detailed breakdown is presented in Table 2.

The utilization of adjuvant and neoadjuvant chemotherapy, adjuvant endocrine therapy, adjuvant targeted therapy, and adjuvant radiotherapy among the patients is documented in Table 2. A correlation heatmap generated through the Pearson correlation coefficient test via SPSS revealed a significant association between breast-conserving therapy (BCT) and a greater rate of radiotherapy than did the mastectomy group. This relationship is statistically significant, with a P value of 0.008. However, based on the available data, there were no statistically significant differences in the rates of chemotherapy (P = 0.286) or endocrine therapy (P = 1.000) between the two groups. The other five studies did not show any notable difference in OS between the two groups. The findings and statistical results from each study are detailed in Table 3. Among the eight studies reviewed, three studies indicated that patients who underwent BCT had better 5-year or 10-year OS rates than did those in the mastectomy group, with these differences being statistically significant, as cited previously^{[5, 12, 14]}. The other five studies did not show any notable difference in OS between the two groups^{[8–11, 13]}. Importantly, the three studies that reported superior OS for the BCT group focused specifically on younger patients with early-stage breast cancer. This suggests that, for this particular group, BCT may provide greater survival benefits than mastectomy does. In summary, when examining patients with breast cancer across various stages, BCT is not associated with worse OS outcomes than mastectomy is.

Table 1

Characteristics of the studies
First author	Public year	Country and diagnostic time	Study type	cases	controls	BC stage	Median follow-up(months/years)	Outcomes measured
Quan ML^[8]	2017	Canada 1994–2003	retrospective cohort	1381	≤ 35y	I-III	11y	HR of 5year and 10year OS
McAree B[9]	2009	UK 2001–2007	retrospective cohort	48	≤ 39y	I-IV	52 m	OR of 5year OS
Sun ZH^[5]	2021	US 1988–2016	retrospective cohort	23810	≤ 40y	I-II	116 m	HR of 10year OS
Maishman T^[10]	2017	UK 2000–2008	Prospective cohort	3024	≤ 40y	I-IV	7.3y	HR of 5year and 10year OS
van der Sangen MJ^[11]	2010	Netherlands 1988–2005	retrospective cohort	1451	≤ 40y	I-II	7.4y	OR of 10year OS
Bantema-Joppe EJ^[12]	2011	Netherlands 1989–2005	retrospective cohort	1453	≤ 40y	T₁N_0 − 1M₀	9.6y	HR of 10yeear OS
Mahmood U^[13]	2011	US 1990–2007	retrospective cohort	14764	≤ 39y	T_1 − 2N_0 − 1M₀	5.7y	HR of 5year and 10year OS
Jeon YW^[14]	2013	Korean 1988–2006	retrospective cohort	3512	≤ 40y	T₁ N_0 − 1M₀	111 m	HR of 10yeear OS

Table 2

T and N stages and adjuvant therapies of the BCT group patients and mastectomy group patients
study	group	Mean age	Total case	T					N
study	group	Mean age	Total case	1	2	3	4	X	0	1	2	3–4	X
Quan ML^[8]	BCT	32.19	793	297	433	29	0	34	324	181	79	0	209
Quan ML^[8]	mastectomy	32.11	588	143	280	121	0	44	170	163	178	0	77
McAree B^[9]	BCT	NA	22	Mean size 2.13					NA	NA	NA	NA	NA
McAree B^[9]	mastectomy	NA	33	Mean size 3.95					NA	NA	NA	NA	NA
Sun ZH^[5]	BCT	NA	10681	6748	3933	0	0	0	7724	2957	0	0	0
Sun ZH^[5]	mastectomy	NA	13129	7350	5779	0	0	0	9073	4056	0	0	0
Maishman T[^10]	BCT	36	1395	Median size 1.90 cm					837	404	99	43	12
Maishman T[^10]	mastectomy	36	1464	Median size 2.85 cm					549	532	246	132	5
van der Sangen MJ^[11]	BCT	37.4	889	610	266	0	0	13	581	304	0	0	4
van der Sangen MJ^[11]	mastectomy	37.2	562	227	313	0	0	22	271	288	0	0	3
Bantema-Joppe EJ^[12]	BCT	NA	909	909	0	0	0	0	693	216	0	0	0
Bantema-Joppe EJ^[12]	mastectomy	NA	544	544	0	0	0	0	357	187	0	0	0
Mahmood U^[13]	BCT	NA	6640	4321	2319	0	0	0	4714	1926	0	0	0
Mahmood U^[13]	mastectomy	NA	8124	4309	3815	0	0	0	4738	3386	0	0	0
Jeon YW^[14]	BCT	36	1951	1951	0	0	0	0	1561	390	0	0	0
	mastectomy	37	1561	1561	0	0	0	0	1079	437	0	0	0

Table 2

(Continued)
First author	group	Adjuvant chemotherapy			Endocrine			Targeted therapy			Neoadjuvant chemotherapy			Radiotherapy
First author	group	yes	no	unknow	yes	no	unknow	yes	no	unknow	yes	no	unknow	yes	no	unknow
Quan ML^[8]	BCT	611	182	0	253	425	115	NA	NA	NA	NA	NA	NA	703	88	0
Quan ML^[8]	mastectomy	432	156	0	213	313	62	NA	NA	NA	NA	NA	NA	304	284	0
McAree B^[9]	BCT	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
McAree B^[9]	mastectomy	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Sun ZH^[5]	BCT	7759	2922	0	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Sun ZH^[5]	mastectomy	8519	4610	0	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Maishman T^[10]	BCT	1055	185	0	893	556	0	149	1246	0	155	900	0	1339	56	0
Maishman T^[10]	mastectomy	1088	100	0	974	490	0	209	1255	0	275	813	0	1006	458	0
van der Sangen MJ^[11]	BCT	378	509	2	171	716	2	NA	NA	NA	NA	NA	NA	889	0	0
van der Sangen MJ^[11]	mastectomy	359	201	2	158	402	2	NA	NA	NA	NA	NA	NA	206	355	0
Bantema-Joppe EJ^[12]	BCT	331	578	0	118	791	0	NA	NA	NA	NA	NA	NA	909	0	0
Bantema-Joppe EJ^[12]	mastectomy	242	302	0	100	444	0	NA	NA	NA	NA	NA	NA	125	419	0
Mahmood U^[13]	BCT	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Mahmood U^[13]	mastectomy	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Jeon YW^[14]	BCT	1342	609	0	1289	662	0	NA	NA	NA	NA	NA	NA	NA	NA	NA
Jeon YW^[14]	mastectomy	997	564	0	985	579	0	NA	NA	NA	NA	NA	NA	NA	NA	NA

Table 3

The observed values and statistical results of each study
first author	BCT group				mastectomy group				HR/rr/OR	P
first author	Total case(n)	BCSS (%)	5-year OS (%)	10-year OS(%)	Total case(n)	BCSS (%)	5-year OS (%)	10-year OS(%)	HR/rr/OR	P
Quan ML2017^[8]	793	NA	87	NA	588	NA	73	NA	HR = 0.98of OS;0.9 of RR	> 0.05
McAree B 2010^[9]	22	NA	90.9	NA	33	NA	69.7	NA	OR of 5-year OS	0.093multivariable analysis
Sun ZH^[5]	10681	10y 89.1	NA	87.8	13129	10y 87.7	NA	85.9	HRof BCSS = 0.917; OS 0.925	BCSS = 0.002;OS = 0.002
Maishman T^[10]	1395	NA	88.7	76.1	1464	NA	79.8	61.8	HR of OS = 0.53	P = 0.081MVA
van der Sangen MJ^[11]	889	NA	NA	74.9	562	NA	NA	71.2	OR of 10year OS	OS P = 0.215 DRFS P = 0.771
Bantema-Joppe EJ^[12]	909	NA	NA	83	544	NA	NA	78	HR of OS = 1.37	P = 0.007
Mahmood U^[13]	6640	10y 85.5; 5y 93.3	92.5	83.5	8124	10y 85.5; 5y 92.5	91.9	83.6	HR of S = 0.93; BCSS = 0.93	P = 0.26OS;P = 0.26BCSS
Jeon YW^[14]	1951	10y 96.9	NA	95	1561	10y 94.9	NA	92.1	HR of OS = 1.487	P = 0.0004

Table 4

Newcastle‒Ottawa Scale (NOS)
Study	selection				comparability	outcome
Study	Representativeness of the exposed cohort	Selection of the nonexposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow-up of cohorts	Quality score
Quan ML[8]	★		★	★	★★	★	★	★	8
McAree B[9]	★		★	★	★	★	★		6
Sun ZH^[5]	★		★	★	★★	★	★	★	8
Maishman T^[10]	★		★	★	★★	★	★	★	8
van der Sangen MJ^[11]	★		★	★	★★	★	★	★	7
Bantema-Joppe EJ^[12]	★		★	★	★	★	★	★	7
Mahmood U^[13]	★		★	★	★	★	★	★	7
Jeon YW^[14]	★		★	★	★★	★	★	★	8

Meta-analysis outcomes:

1 Integral analysis:

1.1 Overall survival rates:

Our meta-analysis encompassed eight studies, contributing a total of ten risk estimates, with two studies providing separate estimates on the basis of different follow-up durations, as illustrated in Fig. 1.

The summary OR points to a notable 33% reduction in the risk of mortality for patients who underwent BCT compared with those who had a mastectomy (SOR = 1.33; 95% CI: 1.07–1.65), as depicted in Fig. 1. These findings suggest that patients who receive BCT have improved overall survival, particularly in terms of 10-year OS (OR = 1.30; 95% CI: 1.00–1.69). However, there was significant heterogeneity among the studies (I² = 94.2% and chi-square P = 0.000).

1.2 Leave-one-out sensitivity analysis

The leave-one-out sensitivity analysis demonstrated that the overall odds ratio was stable, indicating that no single study disproportionately affected the aggregate outcome.

1.3 Egger’s test for publication bias:

The outcomes of this test are as follows: Beta1 = -2.20, SE = 1.172, z = -1.88, p = 0.0599. The p value is marginally above the threshold for significance, hinting at a potential small-study effect. Nonetheless, it does not conclusively indicate the presence of publication bias.

In summary, despite considerable heterogeneity, the summary OS result is fairly reliable, lending credence to the conclusion that BCT may be associated with better overall survival outcomes than mastectomy is.

1.4 SPSS Correlation Analysis Heatmap:

OS was found to be positively correlated with the radiotherapy rate (radio_rate) (0.52), suggesting that a higher rate of radiotherapy may positively influence overall survival.

OS was positively correlated with the proportion of T1 stage tumors (T1 rate) (0.30), indicating that a higher rate of T1 stage tumors may be associated with better overall survival.

OS was positively correlated with the rate of negative lymph nodes (N0 rate) (0.36), which implies that a higher proportion of negative lymph nodes might be linked to improved overall survival.

There was a negligible correlation between OS and the chemotherapy rate (chemo_rate) (-0.01) and a weak negative correlation between OS and the endocrine therapy rate (endocrine_rate) (-0.09), indicating no strong association.

An increase in the radiotherapy rate may increase postoperative OS. However, as the standard treatment protocol, BCT should be combined with postoperative radiotherapy. Ideally, the rate of radiotherapy following BCT should be 100%, which theoretically exceeds the rate for the mastectomy group and surpasses the radiotherapy rates available in the data analyzed in this study. Therefore, the combination of BCT with postoperative radiotherapy, in an ideal scenario, could further increase the radiotherapy rate compared with that of the mastectomy group, thereby enhancing OS and achieving a more advantageous OS than what this study presents. Consequently, the difference in radiotherapy rates between the two groups does not affect the conclusions of this study regarding the impact on OS.

1.5 Meta-regression analysis:

The meta-regression analysis delves into the potential origins of heterogeneity by scrutinizing study-level covariates, including 'Nstage' (lymph node stage) and 'Tstage' (tumor stage). The findings are as follows:

'Nstage': The coefficient is -0.1317 with a p value of 0.844, which implies that there is no significant effect on the effect size.
'Tstage': Similarly, the coefficient is 0.2857, with a p value of 0.512, indicating no significant influence on the effect size.

Despite these findings, the residual heterogeneity is notably high, as evidenced by (Q_res = 167.49, p = 0.000). This persistent heterogeneity suggests that there may be other unmeasured factors at play that contribute to the variability observed across studies.

Although the heatmap from the correlation analysis suggested a relationship between OS and tumor stage and lymph node status, the regression analysis ruled out the impact of differences in T stage and N stage among the included studies on OS.

2 Subgroup analysis

2.1 Subgroup analyses stratified by T stage:

This forest plot presents a comparative analysis of overall survival rates among breast cancer patients who underwent BCT versus mastectomy, categorized by tumor stage ranges: T1, T1-2, and T1-3, as shown in Fig. 7.

T1 Stage: The data suggest that BCT may confer a superior overall survival rate compared with mastectomy. (OR = 1.49 95% CI: 1.23–1.80) I2 = 0, indicating the absence of heterogeneity among the studies. Compared with patients who underwent mastectomy, patients who received BCT experienced a 49% enhancement in overall survival.

T1-2 Stage: At this stage, there is no significant disparity in overall survival between the two surgical approaches. However, a high level of heterogeneity was observed, with an I² value of 92.7%.

T1-3 Stage: Similarly, no substantial difference in overall survival was detected (OR = 1.73 [0.92, 3.25]), I2 = 95.7%, and the I² value was 95.7%, indicating considerable uncertainty in the findings due to high heterogeneity.

In summary, the aggregate effect size encompassing all tumor stages demonstrated an OR of 1.33, with a confidence interval ranging from 1.07–1.65. This statistic suggests that patients who undergo BCT exhibit enhanced overall survival in comparison with those who undergo mastectomy, with particularly notable benefits for individuals presenting with smaller tumors, specifically those measuring less than 2 centimeters in diameter. For this subset of patients with diminutive breast tumors, BCT appears to confer substantially greater advantages. Conversely, in the case of tumors exceeding 2 centimeters in size, there is no discernible survival benefit of BCT over mastectomy. Nonetheless, it is important to emphasize that BCT does not result in inferior overall survival rates compared with mastectomy, at least for patients with breast cancer staged from T1 to T3, despite the considerable heterogeneity observed across the studies.

This comprehensive analysis underscores the potential of BCT to provide superior survival outcomes for early-stage breast cancer patients, especially those with smaller tumors, while also highlighting the need for further research to address the variability in results and to better understand the factors influencing treatment efficacy.

2.2 Subgroup analyses stratified by N stage:

For the lymph node stage N0–1 subgroup, the combined effect size OR = 1.19 [0.99, 1.44]. This is accompanied by a significant level of heterogeneity, denoted by an I² value of 91.1%, as shown in Fig. 8. These findings imply that there is no discernible advantage in OS for N0-1 patients who receive BCT compared with those who undergo mastectomy.

In the lymph node stage N0–3 subgroup, the combined effect size OR = 1.73 [0.92, 3.25]. The heterogeneity in this subgroup was substantial, as indicated by an I² value of 95.7%. The results do not indicate a statistically significant improvement in OS for BCT over mastectomy in patients with varying degrees of axillary node involvement, up to and including N0–3.

When the overall effect size across all lymph node stages was considered, the OR = 1.33 [1.07, 1.65]. This suggests a trend toward improved overall survival for patients who undergo BCT compared with those who undergo mastectomy. However, it is important to note that no significant benefit is observed within any specific subgroup defined by lymph node stage. The overall analysis takes into account a wider array of contributing factors, including adjuvant treatments and tumor dimensions, thus providing a more comprehensive reference.

BCT is a localized treatment approach that aims to preserve noncancerous breast tissue while still effectively addressing cancer. This method is widely recognized for its ability to achieve more favorable cosmetic outcomes, minimize tissue damage, and reduce the incidence of complications. It is generally accepted that individuals who opt for BCT tend to experience better physical and psychological well-being, enhanced social functionality, and an overall higher quality of life than those who undergo a mastectomy. BCT offers a balance between effective cancer treatment and preservation of the natural appearance of the breast, contributing positively to a patient's holistic health and self-esteem^{[15, 16]}. The long-term survival benefits of BCT for young women with breast cancer remain a contentious issue, especially with advancements in radiation therapy and the anticipation of extended life postdiagnosis. Despite the potential for better physical and psychological outcomes, the debate persists, as the medical community has evaluated the impact of BCT over time.^[5] In the 1990s, the rates of BCT rose rapidly because of the main guidelines for early-stage (stage I or II) breast cancer on the basis of several randomized controlled trials. ^{[1, 17]} The proliferation of MRI technology and

Advancements in breast reconstruction techniques since the 21st century have contributed to a decline in the adoption of breast-conserving therapy (BCT)^{[18, 19]} This meta-analysis of breast surgery has been performed on all pathology stages of young women with breast cancer. In this study, young women with higher tumor burdens, characterized by larger sizes and increased lymph node involvement, were more likely to undergo mastectomy. This preference may stem from the tendency for younger patients with breast cancer to exhibit more aggressive traits and present at advanced stages. Historically, younger breast cancer patients have also been noted to face a greater risk of local recurrence than their older counterparts ^{[6, 20]}. Significantly, the 2005 National Comprehensive Cancer Network (NCCN) guidelines highlighted an age less than 35 years as a mastectomy indication, potentially leading to a higher mastectomy rate among young breast cancer patients at that time. However, with the increased participation of young patients in medical decision-making, coupled with emerging evidence demonstrating superior survival outcomes for BCT over mastectomy in real-world settings for early-stage breast cancer, perspectives on treatment choices have evolved. ^{[5, 17, 21]} The reasons are not yet clear or may be related to a better quality of life for patients with BCT and advancements in radiotherapy and systematic therapy. ^{[22, 23]} Recent advancements in surgical techniques, meticulous control of resection margins, and radiotherapy have significantly lowered the recurrence rates of breast cancer. Systemic therapies have also seen substantial progress, with enhancements in chemotherapy, endocrine, targeted, and immunotherapies. These improvements are especially crucial for young women under 40 years of age, who are often more prone to high-risk tumor phenotypes. ^{[6, 24]} The survival differences between BCT and mastectomy in young women still need to be investigated.

According to the analysis of individual experimental results, the 5-year or 10-year OS of patients in the BCT group was no shorter than that of patients in the mastectomy group. Even the BCT group was better than the mastectomy group in some experimental results. Our findings suggest that BCT offers a survival advantage over mastectomy, with a combined effect size OR = 1.33 [1.07, 1.65] for both 5-year and 10-year OS. Notably, the 10-year OS rate significantly improved with BCT (OR = 1.30 [1.00, 1.69]). The high heterogeneity (I2 = 94.2% and chi-square P = 0.000) indicates variability in the study populations, methodologies, N stage, adjuvant treatment and follow-up durations. Subgroup analysis revealed better OS for patients who underwent BCT than for those who underwent mastectomy, especially for young T1 patients. For the T1 subgroup patients, BCT improved OS by 49% (OR = 1.49 95% CI: 1.23–1.80; I2 = 0), with no heterogeneity.

Some studies have reported that BCT and mastectomy are equivalent^{[18, 25]}. For example, Cao et al^[26] conducted a comprehensive 15-year follow-up study, comparing outcomes among 616 women under the age of 40 with those of early-stage breast cancer patients who underwent breast-conserving therapy (BCT) with those of 349 patients who received mastectomy. Those findings revealed no significant differences in overall survival (OS), local relapse-free survival, or distant relapse-free survival between the two cohorts. Similarly, Quan et al^[8] analyzed data from 1381 patients under the age of 35 and confirmed that, in this very young breast cancer population, BCT did not confer any survival disadvantage compared with mastectomy. However, it is worth noting that other studies have demonstrated improved survival outcomes with BCT. ^{[4, 8, 12]} In an analysis of 11,859 patients under 40 from the

In the National Cancer Database between 2004 and 2014, Lazow et al.^[27] reported that BCT was associated with significantly increased 10-year survival compared with unilateral and bilateral mastectomy. Lazow et al.^[27] and Yu et al.^[28] focused on young patients with early-stage breast cancer and conducted a population-based survival assessment for breast surgery. For stage 1 (T1N0M0) young patients, BCT was associated with significantly increased 10-year survival relative to bilateral mastectomy (HR 2.30 [95% CI: 1.61‐3.27], P < 0.001). Among stage I young breast cancer patients, BCSS at 10 years was 91% in the BCT group versus 86% after mastectomy.^[28] The results also revealed greater OS in young women who received BCT than in those who underwent mastectomy. After various confounding factors, such as histological grade, T stage, lymph node status, ER status, and HER-2 status, were excluded from multivariate analysis, BCT still had survival benefits for BCSS patients (HR: 0.917; 95% CI: 0.846–0.995, P = .037) and OS (HR: 0.925; 95% CI: 0.859–0.997, P = 0.041). This meta-analysis compared BCT and mastectomy in breast cancer patients. BCT has clear advantages over mastectomy, especially for T1-stage patients, at the 10-year follow-up. However, for T1-4 stages, all N stages and 5-year follow-ups, BCT offers no survival advantage but also no disadvantage compared with mastectomy. In summary, BCT is a viable option for breast cancer patients, particularly early-stage patients, and long-term monitoring is needed.

Several limitations should be acknowledged in our analysis. First, the integration of seven retrospective cohort studies and one prospective cohort study introduces potential biases stemming from imbalanced prognostic factors, including statistical methodologies, geographical regions, racial diversity, inclusion criteria, sample size, data quality, comorbidities, and subsequent chemotherapy and endocrine therapies. Second, the absence of HER-2 status data in the database has resulted in a significant lack of relevant information for most patients, along with other crucial details such as Ki-67 levels, neurovascular invasion status, and other relevant aspects. Third, our analysis did not extract data on systemic treatments such as chemotherapy, endocrine therapy, or targeted therapy, limiting our understanding of their impact. Moreover, the absence of survival data on relapses undermines our ability to comprehensively assess the effects of adjuvant therapies on overall survival (OS) between the two surgical methods. Notably, the BCT group had a notably greater proportion of patients receiving adjuvant radiotherapy, which correlated positively with OS, further complicating the interpretation of the results. Additionally, the incomplete adoption of targeted therapy, which gained widespread use globally in 2007, introduces another layer of data gap that could affect our findings.

The improved survival observed in BCT recipients may stem from differences in adjuvant therapies, notably radiotherapy. However, our study's heatmap indicates that chemotherapy and endocrine therapy had minimal impacts on OS, and their inclusion should not skew comparisons between BCT and mastectomy, as per National Comprehensive Cancer Network guidelines, which do not differentiate systemic therapy on the basis of surgical approach. While chemotherapy regimens were not fully recorded, acknowledging potential disparities in systemic therapies such as radiotherapy between the BCT and mastectomy groups, it is important to note that with the standardization of systemic therapies, the BCT group's radiotherapy rate would likely exceed that of our study population, potentially increasing OS benefits. Thus, our conclusion remains robust: BCT offers a survival advantage comparable to that of mastectomy for young breast cancer patients, especially those with T1-stage disease, mitigating overtreatment concerns.

In summary, this meta-analysis underscores BCT as a viable first-line treatment option for young breast cancer patients, emphasizing the need for individualized treatment plans that balance overtreatment risks with quality of life considerations. Age should not be the sole determinant of BCT. Further prospective studies are warranted to evaluate BCT benefits in young patients, explore heterogeneity factors and long-term outcomes beyond 10 years, and integrate genetic testing into treatment decisions and survival predictions.

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The authors declare no competing interests.

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Comparative Overall Survival of Breast Conservation Therapy and Mastectomy in Young Women with Breast Cancer: A Comprehensive Systematic Review and Meta-Analysis

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