Surgical reduction in chest wall disease to prolong survival in breast cancer patients: a retrospective study

Introduction

Female breast cancer (BC) was the most commonly diagnosed cancer worldwide in 2020, representing 11.7% of all cancer cases, with an incidence and mortality of 24.5% and 15.5%, respectively (1).

Approximately 5–35% of patients with BC develop locoregional recurrence alone or with distant metastases (2-5), and approximately 11% have persistent chest wall progression (6). Recurrent/metastatic BC in the chest wall is a significant problem and a very poor prognostic sign (7).

However, patients with chest wall recurrence often have heterogeneous characteristics, and not all present poor prognosis (8). A study revealed that local therapy including surgery resection of the chest wall lesion may benefit certain patients (9). A systematic review from Wakeam et al. revealed that, in selected chest wall recurrence patients undergoing chest wall resection, long-term survival approached 40–50% at 5 years and included some patients in whom long-term remission and even cure can be achieved (10). Although surgery is suggested for patients with chest wall recurrence (11), many such as who with multiple lesions or in sites that are not suitable for surgery cannot undergo complete chest wall surgery.

For metastatic breast cancer (MBC) patients with not only chest wall disease and who have already undergone curative treatment for the primary disease, systemic methods should be the first to be considered. However, for patients suffering from compression, ulceration, and pain of the chest wall disease, palliation could be considered when other metastatic sites are not immediately life-threatening.

Although previous studies have discussed the benefit of local surgery among a fraction of patients with chest wall disease (12,13,20-23), the results were controversial. The inconsistent results may due to heterogeneous characteristics among patients received surgical resection. Whether surgical reduction for chest wall disease to reduce tumor burden influences survival outcome for this group of patients is still a question that clinical doctors face frequently. Therefore, the main objective of the present retrospective study was to examine the overall survival (OS) of patients who progressed firstly to the chest wall with or without surgical tumor reduction after previous treatment of primary BC. We present the following article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-22-246/rc).

Methods

Study design and participants

The current study retrospectively reviewed the medical data of Chinese female patients with the chest wall as the first recurrent/metastatic site after treatment for the primary disease at the Department of Breast Oncology, Peking University Cancer Hospital & Institute between January 2012 and December 2018. Patients meeting all of the following criteria were included: non-stage IV BC at initial diagnosis, undergone curative surgery for primary disease, and chest wall was the only site of disease progression or as one of the sites of metastasis. Patients were excluded from the study if they were male, had a serious systemic disorder, and had a second primary malignancy.

Characteristics and follow-up

For all included patients, clinicopathological data, including age at initial diagnosis, TNM stage, the pathological parameters, and treatment of the primary disease as well as of the progressed disease were recorded and analyzed. Estrogen receptor (ER), progestogen receptor (PR) and HER2 status were determined by immunohistochemistry (IHC). Positivity was established at least 1% of cells staining positive for ER or PR. Hormone receptor (HR) positivity was defined as positivity of either the ER or PR. The HER2 status was considered positive if the IHC score was 3+ or if an IHC score of 2+ was confirmed by fluorescence in situ hybridization (FISH). Triple-negative breast cancer (TNBC) was defined as ER negative, PR negative and HER2 negative. The primary endpoint was the OS, defined as the time from the diagnosis date of breast cancer until death from any cause or the last follow-up date, whichever occurred first. The disease-free survival (DFS) was defined as the time from the diagnosis date of breast cancer until the first diagnosis of tumor progression.

The primary aim of the study was to compare the OS between patients with and without surgical reduction for chest wall tumor.

All included patients were followed up regularly until death or study data cutoff (31 July 2021). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Peking University Cancer Hospital & Institute (No. 2016YJZ19) (Beijing, China). Individual consent for this retrospective analysis was waived.

Statistical analysis

Categorical variables are presented as frequency and percentage, while continuous variables are presented as mean (SD) or median (IQR), wherever appropriate. The statistical significance for categorical variables was tested by the χ² test and for continuous variables was tested by the unpaired t-test [for mean (SD)] or the Mann-Whitney U test [for median (IQR)]. OS was primarily described using the Kaplan-Meier estimator for each group, with the statistical significance between groups being tested by the log-rank test. The hazard ratios (HRs) for OS and 95% confidence interval (CI) were estimated using the Cox proportional-hazards model. Missing data was excluded from the analysis. Specifically, variables with imbalance distributions at baseline or statistically significant associations (P<0.05) in univariate analysis were included in the multivariate Cox model. All statistical analyses were conducted with SPSS 22.0 statistical software (SPSS, Chicago, IL, USA). All reported P values are two-sided, with P<0.05 being considered statistical significance.

Results

Patient information

A total of 198 female BC patients from the Department of Breast Oncology, Peking University Cancer Hospital & Institute between January 2012 and December 2018 (median age 48 years; range, 22–73 years) were enrolled. All those with the chest wall as one of the first metastatic sites were analyzed. The median follow-up after the initial diagnosis of BC was 93.3 months, and the median follow-up after recurrence/metastasis was 49.0 months.

The patients’ characteristics and treatment are presented in Table 1. All patients had primary tumor surgery and there were none with de novo stage IV. As the molecular type of primary BC, 36 patients (18.2%) were diagnosed with triple-negative breast cancer (TNBC), 138 (69.7%) had hormone receptor positive (HR+) BC and 54 patients (27.3%) had human epidermal growth factor receptor 2 (HER2) positive BC. Furthermore, a total of 106 patients (53.5%) had stage I–II disease and 73 patients (36.9%) had stage III disease. Tumors >2 cm were detected in 58.6% (n=116) of the patients. A total of 129 (65.2%) patients had axillary lymph node (LN) metastasis. A total of 174 (87.9%) patients received adjuvant chemotherapy. Patients who were eligible (n=70, 35.4%) received radiotherapy after primary surgery. There are 101 (51.0%) patients on hormone therapy, and 25.9% of patients (14/54) with positive HER2 amplification received standard anti-HER2 therapy. A total of 117 patients (59.1%) had a DFS >24 months following diagnosis.

The chest wall as the only site of recurrence occurred in 139 patients (70.2%), and the other 59 (29.8%) patients not only had chest wall recurrence but also other sites of metastasis, the most common being the LNs (50/59, 84.7%), both regional and distant. Other metastatic sites included the bone (12/59, 20.3%), lung (8/59, 13.6%), liver (11.9%, n=7), pleura (5.1%, n=3), contralateral breast (3.4%, n=2) and adrenal (1.7%, n=1). A total of 17 patients (28.8%) had ≥3 metastatic sites.

As treatment for disease progressions, the patients received a median of three lines of systematic therapy, including chemotherapy, hormonal therapy and targeted therapy. There were 88 (44.4%) patients who underwent surgical reduction for chest wall. While, 75/139 (54.0%) patients with the chest wall as the only recurrent site had surgical reduction, compared with 13/59 (22.0%) of those with multiple metastatic sites. After recurrence/metastasis, a total of 88 (44.4%) patients had radiotherapy as local treatment; most of the patients (93.9%) had systematic treatment at first line. There were 19.7% (39/198) patients treated with antiangiogenesis therapy.

Survival

Patients undergoing surgical reduction for chest wall disease had better OS compared with patients without. The median OS was significantly longer for patients who had surgical reduction of chest wall disease (n=88) than for those who did not (n=110) [194.2 months (95% CI: 140.4–247.9 months) vs. 102.7 months (95% CI: 79.7–125.7 months), respectively, P=0.001, Figure 1].

Figure 1 Kaplan-Meier curve of OS in patients who did or did not have surgical reduction. OS, overall survival.

Univariate analysis of the correlation between characteristics as well as treatment and OS was performed. The results showed significant prolongation of median OS in patients with surgical reduction of chest wall disease (P=0.001), HR+ status (P=0.000), non-TNBC (P=0.001), negative axillary LN metastasis (LNM) of the primary tumor (P=0.020), TNM stage I–II (P=0.000), chest wall recurrence only (P=0.014) and DFS >24 months (P=0.000) (Table 2).

Variables with imbalance distributions at baseline or statistically significant associations (P<0.05) in univariate analysis were included in the multivariate Cox model. The results showed that DFS >24 months and surgical reduction of disease remained independent predictive factors of OS (Table 3).

A total of 88 patients had surgical reduction and there was no significant difference between patients who did (54/88) or did not (34/88) receive radiation therapy for the chest wall after surgical reduction [197.7 months (95% CI: 143.5–251.9 months) vs. 194.2 months (95% CI: 73.1–315.3 months), respectively, P=0.483].

In a subgroup analysis of patients with only chest wall recurrence, those who had surgical reduction (n=75) had a longer median OS [203.6 months (95% CI: 159.5–247.7 months) vs. 82.8 months (95% CI: 47.6–117.9 months), respectively, P<0.001, Figure 2].

Figure 2 Kaplan-Meier curve of OS comparing patients with chest wall recurrence only who did or did not have surgical reduction. OS, overall survival.

Univariate analysis of the correlation between characteristics as well as treatment and OS was performed in patients with only chest wall recurrence. The results showed a significant prolongation of median OS in those with surgical reduction of chest wall disease (P=0.000), HR+ status (P=0.000), non-TNBC (P=0.003), TNM stage I–II (P=0.000) and DFS >24 months (P=0.000) (Table 4).

Multivariate analysis performed with the factors with P value <0.05 in the univariate analysis showed that TNM stage I–II, DFS >24 months and surgical reduction of chest disease remained independent predictive factors of OS in patients with chest wall metastasis only (Table 5).

In patients with only chest wall disease as BC progression, a total of 75 underwent surgical reduction. There was no significant difference between patients who did (49/75) or did not (26/75) receive radiation therapy for the chest wall after surgical reduction [203.6 months (95% CI: 101.0–306.2 months) vs. 205.8 months (95% CI: 110.5–301.1 months), respectively, P=0.711]. Additionally, in patients who had both adjuvant radiation therapy and surgical reduction for the chest wall, there was no significant difference between patients who did (14/26) or did not (12/26) receive radiation therapy for local recurrence after surgical reduction [246.1 months (95% CI: 133.5–358.8 months) vs. 206.4 months (95% CI: 0.0–445.7 months), respectively, P=0.623].

However, whether patients did or did not have surgical reduction of chest wall disease did not influence survival outcome among patients with multiple metastatic sites.

Subgroup analyses (Figure 3) showed that OS was statistically longer in the chest wall disease surgical reduction group than in the no reduction group with respect to HR(−) (hazard ratio 0.32; 95% CI: 0.15–0.71; P=0.005), HER2(−) (hazard ratio 0.45; 95% CI: 0.29–0.69; P=0.000), TNBC (hazard ratio 0.23; 95% CI: 0.07–0.78; P=0.003), DFS >24 months (hazard ratio 0.47; 95% CI: 0.28–0.78; P=0.004), and chest wall disease only (hazard ratio 0.46; 95% CI: 0.29–0.72; P=0.001). Patients in the surgical reduction group had better OS whether or not they received adjuvant radiation therapy.

Figure 3 Forest plot of OS subgroup analyses with hazard ratios. HR, hormone receptor; HER2, human epidermal growth factor receptor 2; RT, radiotherapy; DFS, disease-free survival; OS, overall survival.

Discussion

This retrospective study mainly focused on whether surgical reduction of chest wall tumor burden could affect survival in patients with chest wall metastasis in real clinical practice. All the patients enrolled had chest wall lesions, and some of them had multiple metastatic sites.

We found that OS was significantly prolonged in patients who had chest wall disease partly or fully removed, which means local surgical burden reduction should be considered when allowed.

In this study, most of the patients had chest wall recurrence only, which was totally removed or reduced surgically according to the indication.

Previous studies have focused mainly on surgery of chest wall recurrence (12,13) or primary breast tumor in de novo metastatic patients (14-20). So we chose treatment of patients with only chest wall recurrence as our study topic. In the National Comprehensive Cancer Network (NCCN) consensus (11), patients with only local recurrence should be considered for surgical resection with radiation therapy in mastectomy-treated and mastectomy in breast-conserving patients, respectively. But the NCCN still emphasizes the importance of individual treatment in this group of patients.

Our study found that in patients with only chest wall recurrence, the median OS was significantly improved in the surgical reduction group in compared with the nonsurgical group, which was consistent with the NCCN recommendation that surgical treatment of locally recurrent disease is of great importance (11). In our subgroup analysis, we did not find any difference of OS whether patients had radiation therapy or not after surgical reduction, but this result may be limited by the sample size.

For chest wall recurrent disease, previous research on whether patients should undergo chest wall surgical resection has been mostly retrospective. From small-sample research concerning the benefits of chest wall resection, the overall 5-year survival was 18–25% (13,21). However, results from studies with two comparative groups are controversial. In the study by Shen et al. (22), the difference in 5-year survival was not statistically significant between the surgical group (30.6%) and nonsurgical group (49.6%), with a nearly 20% decrease in patients who underwent surgery. This relatively big difference might due to the aggressive characteristics of their surgical group with mainly TNBC patients. In the latest research from Shanghai (23), Wu et al. retrospectively developed a nomogram based on clinicopathological factors, dividing patients with local recurrence into low- and high-risk subgroups. They found that local treatment, especially surgery, after local recurrence was the optimal choice for patients with lower risk, whereas systemic treatment should be considered for patients with higher risk. This finding reminds us of the great importance of individual patient selection for surgery.

In our subgroup analysis exploring patients who could benefit from surgical reduction, we found those with DFS >24 months could gain longer survival outcome. This finding was consistent with Wakeam et al. (10) who systematically reviewed the literature on chest wall resection for recurrent BC. From the 48 studies they searched, a disease-free interval (DFI) >24 months was one of the factors consistently associated with improved outcomes after resection of recurrence (13,24-26). These findings challenge the impression that all chest wall recurrences portend a uniformly poor prognosis. In a certain selected group, resection or surgical reduction may be warranted (9).

Our study group included stage IV patients with multiple metastases besides the chest wall after treatment of the primary tumor. Because this patient population is still considered incurable, the primary goal of treatment is to extend life expectancy and improve quality of life. Systemic therapy is the current standard of care, and surgery is not recommended except for those patients requiring palliation of symptoms or with impending complications such as skin ulceration and bleeding (11).

But what about the role of local tumor burden release by surgery in multi-site metastasis patients? In the subgroup analysis (n=59), we did not find any relationship between lesion removal and OS. However, tumor burden reduction (27) did indeed have something to do with OS. From the limited number of previous prospective studies, research from Turkey reported that the initial surgery group showed a statistically significant improvement in 5-year survival of de novo stage IV BC (20). Meanwhile, they found that patients in several groups could benefit from surgery. So, combined with the results from the largest meta-analysis concerning locoregional therapy of primary tumor in de novo stage IV BC, the local therapeutic option should be considered in selected patients after multidisciplinary discussion (28).

Because of the sample size, there were only 13 multi-site metastasis patients who had undergone tumor burden reduction in our study. It was difficult to determine the benefit for clinical outcome from this study. Besides, a potential bias may have been created by the choice of systemic treatment, which was dependent on the site of recurrence/metastasis.

In conclusion, the present study in patients with chest wall disease found that OS was significantly prolonged in patients who had surgical reduction, especially in patients with only chest wall recurrence. Breast cancer patients with chest wall recurrence could benefit from surgical reduction with a prolonged OS. In a certain selected group, such as patients with DFS >24 months, resection or surgical reduction may be warranted in real clinical practice.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-22-246/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-22-246/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-246/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Peking University Cancer Hospital & Institute (No. 2016YJZ19) (Beijing, China). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: K. Brown)