Local surgery improves survival in elderly patients with stage IV breast cancer: a population-based retrospective cohort study

Introduction

In the United States, breast cancer predominantly affects the elderly. As of 2019, 54% of breast cancer cases are diagnosed in women older than 60 years, and 72% of breast cancer deaths occur in this age group. The median age at which women are diagnosed with breast cancer is 62 years (1). The treatment of stage IV breast cancer is a comprehensive treatment with chemotherapy, targeted, endocrine, and other systemic treatments as the main modalities. The prognosis is poor, and the 5-year overall survival rate is about 38% (2). The role of local therapy in stage IV breast cancer is controversial. The number of prospective studies is limited and the results are inconsistent (3-6). These studies have some flaws. The imbalance of baseline variables, insufficiency of system therapy, and high tumor burden are thought to lead to bias. Whether it improves patient survival and prognosis, or which groups of patients benefit from it, remains to be determined (7). In our previous retrospective analysis of the whole population, local surgery improved 5-year survival in patients with stage IV breast cancer, and radiotherapy seemed to further improve this index (8). However, elderly patients are a special group. The patients had more comorbidities and less desire for active treatment. The disease itself is often of the hormone receptor positive type and sensitive to endocrine therapy (9). As systematic treatments continue to improve, little is known about the role of local therapy in elderly breast cancer patients. Whether systemic therapy combined with local therapy can benefit, and how to select patients who need local therapy has not been clarified.

Although there was selection bias in the retrospective analysis, it is very difficult to conduct a large prospective study involving elderly patients, especially related to surgery. Surveillance, Epidemiology, and End Results (SEER) database collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 34.6% of the U.S. population so that it has a rich resource of cases. Hence, we hope to retrospectively analyze data from the it to elucidate the effect of local therapy on the metastatic elderly breast cancer cohort. Through stratified analysis, we hope to further understand which type of elderly patients are more likely to benefit from local therapy. We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5124/rc).

Methods

Data source and study population

A retrospective cohort study was performed with data extracted from the SEER 21 registry (November 2020 submission) database using SEER*Stat Software version 8.3.9 software. The inclusion criteria were listed as followed: (I) histologically diagnosed stage IV breast cancer according to the 7th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification between 2010 and 2015; (II) aged 65 years or older; (III) underwent chemotherapy. Patients were excluded for the following reasons: (I) male patients; (II) patients with T0 local disease; (III) cases combined with or secondary to other tumors; (IV) unavailable information about locoregional therapy; (V) information on distant metastatic involvement was missing; (VI) incomplete follow-up data. A total of 1,900 cases entered the final analysis (Figure 1). All data obtained included age at diagnosis, race, tumor grade, molecular subtype, TNM stage, metastatic site, treatment (including local surgery and radiotherapy), and follow-up information. SEER data are publicly available, and a signed research data agreement form was required to access the database. Institutional review board approval was waived since it is a medical record-based study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Figure 1 Study flow chart.

Statistical analysis

Cause-specific survival (CSS) was defied as the time from the date of diagnosis to the date of death attributed to breast cancer. The CSS was plotted using Kaplan-Meier (KM) curves, and differences between groups were assessed using log-rank test. Variables that significantly affected CSS were investigated by multivariate analyses according to the Cox regression model. Since death from other causes was the competing risk factor for cancer-specific death, Fine and Gray’s competing risks regression was also used to identify potential risk factors associated with CSS, with results determined by subdistribution hazard ratio (SHR) and 95% confidence interval (CI). Competing risk analyses were also used to generate cumulative incidence graphs of death probability. All statistical analyses were carried out using R statistical software (version 4.1.2; The R Foundation for Statistical Computing) and Stata (version 13.0; StataCorp LLC, College Station, TX, USA). All tests were two sided, with an priori significance level set at P<0.05.

Results

Clinicopathological characteristics

A total of 1,900 patients were enrolled in the study after screening according to the inclusion criteria. The median age was 71 (range, 65 to 95) years. The White race accounted for 79.7% of cases, followed by the Black race at 14.2%. The primary breast lesions were mostly large masses (T3–4 comprised 52.5%), and regional lymph node metastasis was also common, mainly N1 (43.1%). The main molecular subtypes were luminal type (61.6%). Human epidermal growth factor receptor 2 (HER2) over-expression and triple-negative breast cancer (TNBC) type (10.3% and 19.1%, respectively) were less common. The histopathological grade of tumors was mostly poorly differentiated (45.3%). Bone was the most common site of metastasis (29.5%), followed by the lung (14.4%); brain metastasis was rare (1.1%). The proportion of patients receiving local treatment was low, with 636 patients (33.5%) receiving surgery and 280 patients (14.7%) receiving radiotherapy (Table 1).

CSS and cumulative probability

The median follow-up time for all patients was 18 (range, 1–83) months with a 5-year CSS of 27.5%. Patients who underwent local surgery had a higher 5-year CSS than those who did not (36.5% vs. 22.4%, P<0.001) (Figure 2A). The cumulative mortality curve showed that 5-year tumor-related mortality was lower in patients who underwent local surgery than in those who did not (63.5% vs. 77.6%, P<0.001; SHR, 0.628; 95% CI, 0.551–0.717) (Figure 2B).

Figure 2 Survival curves of patients with and without surgery. (A) CSS; (B) cumulative mortality. CSS, cause-specific survival.

The 5-year CSS of patients who received radiotherapy was comparable to that of those who did not (28.9% vs. 26.5%, P=0.060) (Figure 3A). The cumulative mortality rates of the two groups were similar (71.1% vs. 73.5%, P=0.101; HR, 0.869; 95% CI, 0.736–1.028) (Figure 3B). Further subgroup analysis based on clinicopathological data showed that patients of all ages except ≥85 years could benefit from surgery (all P<0.05). In terms of the histopathological grade, all patients except undifferentiated patients could benefit from surgery. Meanwhile, patients with all molecular subtypes could benefit from surgery except for those whose type was unknown (all P<0.05). Besides, only patients with simple bone metastasis could benefit from surgery [P<0.001; hazard ratio (HR), 0.519; 95% CI, 0.394–0.683], but not metastases in other sites (Figure 4). Further subgroup analysis based on clinicopathological data showed that only moderately differentiated (P=0.031; HR, 0.672; 95% CI, 0.469–0.964), luminal A (P=0.025; HR, 0.734; 95% CI, 0.560–0.962), and TNBC (P=0.028; HR, 0.700; 95% CI, 0.509–0.962) can benefit from radiotherapy (Figure 5).

Figure 3 Survival curves of patients with and without radiotherapy. (A) CSS; (B) cumulative mortality. CSS, cause-specific survival.

Figure 4 Subgroup analysis of CSS between surgery and no surgery. CI, confidence interval; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer; CSS, cancer-specific survival.

Figure 5 Subgroup analysis of CSS between radiotherapy and no radiotherapy. CI, confidence interval; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer; CSS, cancer-specific survival.

Factors associated with CSS

Univariate analysis showed that age ≥75 years, histological grades of poorly differentiated and undifferentiated, molecular subtype of TNBC, lung, liver, brain, and multiple site metastasis, and no surgery or radiotherapy were associated with poor CSS (all P<0.05); luminal B type was associated with better CSS (P=0.005; HR, 0.766; 95% CI, 0.636–0.922). Further multivariate Cox regression analysis confirmed that surgery was an independent protective factor affecting CSS in elderly patients with stage IV breast cancer (P<0.001; HR, 0.558; 95% CI, 0.485–0.643); radiotherapy was not an independent prognostic factor (P=0.822). Other independent prognostic factors included age, histological grade, molecular subtype, and distant metastasis (all P<0.05, Table 2).

We also performed a multivariate Gray’s competing risk regression model to adjust potential confounding factors (Table 3). The results also showed that surgery (P<0.001; SHR, 0.620; 95% CI, 0.535–0.718) was an independent prognostic factor affecting CSS in elderly patients with stage IV breast cancer; radiotherapy was not significantly associated with CSS (P=0.954; SHR, 1.005; 95% CI, 0.846–1.202).

Discussion

This study shows that characteristically, elderly breast cancer patients are mainly concentrated between 65 and 75 years. At the time of diagnosis, the diameter of the primary breast mass was larger, and the molecular subtype was more commonly luminal type, and less commonly TNBC. This is consistent with the characteristics of elderly breast cancer reported in previous studies (10,11). In terms of the histopathological grade, moderate and poor differentiation accounted for 75.3%, which may be related to the inclusion of the population with advanced disease, and the presence of selection bias.

The role of local therapy in advanced breast cancer is controversial. This study attempted to elucidate the role of local therapy in stage IV elderly breast cancer. Elderly patients, as a heterogeneous group, are often accompanied by complex complications, poor tolerance of therapy, and more careful choice of invasive treatment. In this study, both the Cox model and risk competition model showed that elderly patients with stage IV breast cancer could benefit from surgery, and age was not an absolute taboo for surgery. However, the risk of surgery increases with age, with the highest risk in patients over 85 years of age (12). This is also consistent with the results of our further subgroup analysis, which found that patients over 85 years of age did not benefit from surgery, and this group should be carefully selected for surgery.

Studies without age limitation suggest that patients with oligometastatic breast cancer, especially those with bone metastasis alone, should more actively choose local therapy to improve survival (13,14). This was also replicated in the subgroup analysis of the present study. Elderly patients with bone metastases may benefit from local treatment, but those with lung, liver, and brain metastases do not. Unfortunately, the SEER database could not obtain the tumor load at the site of metastasis and could not determine whether the metastasis was oligometastasis, which reduced the preciseness of the conclusions we obtained. Tumors and metastases are like seeds and soil. Primary therapy can reduce the possibility of tumor metastasis or re-metastasis at the source, eliminate tumor cells and their release of metastatic mediators, thus further controlling the disease (15).

Whether elderly patients can benefit from radiotherapy has been a source of debate. In patients with early-stage breast cancer who are approximately 70 years after breast-conserving surgery, radiation reduces the risk of local recurrence but does not affect long-term survival (16), suggesting that radiation therapy is less effective in elderly breast cancer. The role of radiotherapy in stage IV senile breast cancer has not been described. This study shows that, unlike younger patients (17,18), local radiotherapy does not affect prognosis in older patients with stage IV. However, subgroup analysis suggested that moderately differentiated histological grade seemed to benefit from radiotherapy. There is no literature to support this, and more data are needed. In addition, luminal A and TNBC groups can benefit from radiotherapy. Different researchers have come to different conclusions about whether radiation therapy is better for older patients with luminal A or B. Liu and Chen et al. found that patients with luminal A had a better prognosis and the lowest local recurrence rate compared with other subtypes (19,20). However, Zhi et al. reported that patients with luminal A did not benefit from radiotherapy (21). This phenomenon needs further study and confirmation. A study by Zhang et al. in the SEER database on the role of radiotherapy in stage IV breast cancer also found that patients with TNBC could benefit from radiotherapy (22). TNBC is considered the most immunogenic subtype of breast cancer (23). It has been shown that radiotherapy may stimulate the immune system, increasing the proportion of antigen-experiential T cells to effector memory T cells (24). Once the immune system is activated, increased concentrations of molecules associated with pro-inflammatory immune responses, such as tumor necrosis factor (TNF), can promote antigen presentation, stimulate T cells, and lead to activation of the corresponding immune response and tumor cell death in metastatic TNBC patients (25). These effects make radiotherapy a possible way of collaborating with the immune system, leading to metastatic TNBC benefiting from radiotherapy. In addition, some TNBC patients have BRCA1 gene mutations. The BRCA1 tumor cells are derived from luminal progenitor cells, and Chiang et al. observed that radiotherapy could permanently eliminate luminal ductal epithelial progenitor cells, reducing the risk of recurrence in BRCA1 mutation carriers (26).

Of course, there are some limitations in this paper. Firstly, this was a retrospective study with inevitable retrospective bias. Secondly, specific chemotherapy regimen, efficacy, recurrence, and other data were not obtained from the SEER database for further analysis. Besides, the information database of radiotherapy site is not specified, but this study can explain the role of radiotherapy in stage IV senile breast cancer, regardless of radiotherapy in primary or metastatic lesions.

In general, elderly patients with stage IV breast cancer can benefit from surgical treatment, especially patients with moderate differentiated, luminal A, or TNBC, who can also benefit from radiotherapy. It is necessary to accurately select appropriate groups for local surgery or radiotherapy based on the individual conditions of the elderly to obtain the greatest benefit.

Conclusions

Surgical treatment improves the survival of elderly patients with stage IV breast cancer. Notably, patients with moderate grade in histopathology, molecular typing of luminal A, or TNBC can also benefit from radiotherapy. This study is helpful in selecting the appropriate group for local surgery or radiotherapy according to the individual circumstances of the elderly for maximum benefit.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5124/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5124/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).

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: J. Jones)