The relationship between time to surgery(TTS) after neoadjuvant chemotherapy (NAC)and survival in breast cancer patients: meta-analysis

PURPOSE: This meta-analysis aims to evaluate the impact of delaying surgery in operable breast tumor patients after neoadjuvant chemotherapy (NAC) on survival. METHODS: An electronic literature retrieval was conducted on PubMed/Medline and EMBASE((between January 2000 and June 2020).The primary end point was overall survival(OS),secondary end points included disease-free survival (DFS) or recurrence-free survival (RFS).The HR with 95% condence intervals were calculated using a random-effects or xed-effects model. RESULTS: The combined HR for OS was 1.52(95% CI 1.29-1.78; P = 0.000) by xed-effects model.No statistically signicant heterogeneity was found (P=0.114;I 2 =39.8%).The pooled HR for RFS/DFS was 1.47 (95%CI: 1.27- 1.71,I 2 =61.9%) by random-effects model, with signicant heterogeneity. CONCLUSION: Our meta-analysis revealed a signicant adverse association between longer TTS after NAC and more inferior OS and RFS/DFS in patients with breast cancer.Clinicians and patients should minimize surgical delay after NAC as much as possible. Eight systematic reviews, four studies on metastatic breast


Background
Breast tumor is the most common malignancy in women today,and surgical treatment remains the primary treatment in most patients with breast cancer.Approximately 37-40% of breast cancer patients receive surgery [1]. Most patients begin adjuvant chemotherapy (AC) within a few weeks after breast surgery. However it is unknown whether delayed AC would result in poorer outcomes for breast cancer patients.Several studies have explored the appropriate timing of adjuvant chemotherapy for operative patients with breast cancer, and there is still no consensus on the optimal timing of postoperative AC for breast cancer patients. A systematic review and meta-analysis demonstrated that a longer waiting-time from surgery to AC would lead to worth outcomes, especially in triple-negative breast cancer (TNBC) patients [2].
A variety of clinical trials demonstrated that neoadjuvant chemotherapy (NAC) is a well-established treatment option for patients with locally advanced or inoperable breast tumors [3]. Furthermore,both early-stage and advanced breast tumors can bene t from NAC to increasing breast conservation rates [4].
While there have been few studies investigated the optimal operative time after NAC for patients with operable breast cancer.Our study aims to explore the impact of delaying surgery in operable breast tumor patients after NAC on survival.

Materials And Methods:
Data source: An electronic literature retrieval was conducted on PubMed/Medline and EMBASE((between January 2000 and June 2020).Search terms were used such as "timing to surgery" or "time to surgery" and "breast neoplasm" and "survival" published in English.
Selection criteria: The included literature needs to meet the following criteria: 1) All of the patients received preoperative NAC,the time interval from NAC to surgery was documented. 2) The relationship between the time from NAC to surgery and survival should be reported. 3) The primary end point was overall survival(OS),secondary end points included disease-free survival (DFS) or recurrence-free survival (RFS), 4) The hazard ratio (HR) with 95% con dence intervals (CIs) should be reported directly or su cient data was provided to calculate them. To avoid publication bias, both the fulltext and the summary of the meeting were included in our analysis.Patients would be excluded if they had received AC therapy, had stage IV disease, or had undergone mastectomy at an outside hospital.
Data extraction and quality assessment: Two experienced authors ((S.Y.C and Z.X.G) independently extracted data from the included studies. The data extracted from the literature included: rst author's name, publication year and country, population characteristics, waiting time,HR with corresponding 95%CI, and covariates in the fully adjusted model. RFS were treated as DFS in our analysis because the de nition of RFS was similar to DFS [2]. Waiting time was de ned the time interval from the end of preoperative NAC to initiation of surgery.Several studies had revealed that the earlier surgery was performed after preoperative NAC, the better outcome the patients would get. What's more, due to the impact on survival that caused by a too-short delay (i.e.one week) would so small that could not be observed, we used 4-weeks as cut-off in our metaanalysis.
We used the Newcastle-Ottawa Scale (NOS) criteria to assess the quality of all included studies [5]. Three studies showed high quality (≥8 points) [6], and all studies scored six points or more according to the NOS criteria, indicating the quality of all included studies was good [7]. Any disagreements on the quality assessment and data extraction would be resolved by consensus or consultation of a third party.

Statistical analysis:
We used the software Stata 15.0 to perform statistical analyses. And the I 2 statistic and the Q-test were used to assess statistical heterogeneity. When P > 0.1 and I 2 <50%, we used the xed-effects model, once P < 0.1 and I 2 >50%, the random-effects model was used [8]. Our analysis used funnel plots, the Begg and Egger tests to assess publication bias. Asymmetrical funnel plot and P-value of Egger's test (<0.05) suggested that there was publication bias in all studies [9,10]. For all the statistical analyses, p<0.05 was considered statistically signi cant.

Results
Data synthesis: A total of four hundred and ve potentially relevant publications were found according to our initial search strategy, one hundred and sixteen publications from PubMed/Medline, two hundred and eighty-nine publications from Embase. There were three hundred and one publications after duplicate publications were removed; of these, we excluded two hundred and sixty-eight articles because the title or abstract did not meet the eligibility criteria. Eight systematic reviews, four studies on metastatic breast cancer, and eleven non-neoadjuvant chemotherapy were further excluded. Eventually, nine articles [11][12][13][14][15][16][17][18][19] (eight studies) were identi ed as eligible for our analysis, including eight independent studies for OS, six studies for RFS, and two for DFS [14]. The ow chart of the literature search and study selection is shown in Fig. 1.
Study quality: The eligible studies were conducted in Australia, Saudi Arabia, Italy, Peru, the USA and Canada. The number of participants ranged from 58-1101 per study for 4521 patients across the ten studies. Detailed baseline characters of each eligible study were listed in table 1. Table 2 showed the HR results from each eligible study.
Sensitivity analysis was used to assess the root of heterogeneity. As shown in Fig. 4, the individual data set had no signi cant in uence on the OS and RFS/DFS, demonstrating the reliability and stability of the results in our meta-analysis.
Asymmetrical funnel plot showed in Fig. 5a and P = 0.002 < 0.05 for Egger's test demonstrated that our studies existed publication bias for OS. Statistical tests also showed publication bias for RFS/DFS was found in our study ( p < 0.05 for Egger's test and p = 0.003 for Begg's test), Fig. 5b. Then, trim-and-ll method was conducted to adjust funnel plots [20,21]. Three missing studies were added in analysis of RFS/DFS and four studies in OS, Fig. 6. The recalculated results were still signi cant for RFS/DFS (HR = 1.33, 95% CI = 1.04-1.72; random-effects model; p < 0.01) and OS (HR = 1.38, 95%CI = 1.07-1.78, randomeffects model; p < 0.01), indicating the conclusions in our meta-analysis were stable and reliable.

Discussion
The meta-analysis showed that TTS delays after NAC was positively connected with the risk of death in patients with operable breast cancer. The combined HR demonstrated that OS and RFS/DFS were signi cantly worse in patients with TTS > 4-weeks compared to patients with TTS < 4-weeks (HR = 1.49, P = 0.000, and HR = 1.40, P = 0.000). Therefore, it is responsible for considering that a 4-weeks delay in surgery after NAC is connected with an increase in the relative risk of death of approximately 49%, and 40% for RFS/DFS. As shown in Fig. 4, the asymmetrical funnel plot revealed a publication bias in our meta-analysis. After adjusted by trim-and-ll method, the corrected results of RFS/DFS and OS were still statistically signi cant (HR = 1.33; p < 0.01 and HR = 1.38, p < 0.01, respectively), indicating our results were robust and reliable.
Our meta-analysis had some limitations. Firstly, our nding was based totally on observational studies.
We could not completely rule out the effect of confounding on our analysis. Therefore, the conclusion should be interpreted cautiously. Secondly, due to individual information not available, sub-analyses according to different features failed. Thirdly, different phenotypes of breast cancer would lead to uncertain prognosis;in part,survival is dependent upon breast cancer subtypes [22].However,because of insu cient information provided in the original studies, we did not further explore whether TTS delays after NAC had an impact on the prognosis of breast cancer patients with different hormone receptor and HER2 status. Despite these limitations, our meta-analysis still has crucial clinical directive signi cance. Physicians should minimize surgical delay after NAC for breast cancer patients when possible. Conclusion our meta-analysis revealed a signi cant adverse association between longer TTS after NAC and more inferior OS and RFS/DFS in patients with breast cancer. Clinicians and patients should minimize surgical delay after NAC as much as possible.

Declarations
Ethical approval and consent to participate : All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication:
Not applicable Availability of data and materials: Not applicable Informed consent : The study was approved by the local institutional review board, and the requirement for informed consent was waived because of the retrospective nature of this study.