The timing of surgery for elderly patients with locally advanced breast cancer

Introduction

Breast cancer is the most common malignancy and the second leading cause of cancer death in women (1). As the global population ages and life expectancy rises, the incidence of breast cancer in the elderly is also increasing (2).

Advancements in medical technology have led to earlier detection of breast cancer. With the implementation of cancer screening in various countries, more breast cancer is found by auxiliary examinations such as with ultrasound and mammogram, and the mass may not be identified by clinical physical examination. Given that older than 70 patients are not routinely screened, they are at increased risk of developing advanced breast cancer. Thus, when the elderly population is diagnosed, some of the elderly patients present with locally advanced breast cancer (3).

With the development of diagnostic and treatment technology, the treatment of locally advanced breast cancer has evolved from upfront surgery to neoadjuvant therapy (NAT). NAT represents a significant milestone in breast cancer management as it can reduce the stage of inoperable tumors to operable status, transform patients with large tumors that cannot be breast-conserving into breast-conserving and without axillary lymph node dissection, and obtain the drug sensitivity of tumors by observing the changes of tumors in chemotherapy. Currently, NAT for breast cancer is mainly neoadjuvant chemotherapy, and a small number of patients undergo neoadjuvant endocrine therapy and neoadjuvant radiotherapy. Among them, for NAT in human epidermal growth factor receptor 2 (HER-2) positive patients, chemotherapy combined with targeted therapy significantly improves the pathologic complete response (PCR) rate of patients (4-6).

NAT has become a standard treatment for locally advanced breast cancer (7,8). The greater the tumor burden, in clinical practice, drugs for more intensified chemotherapy are often required. There is evidence of a dose-response relationship with chemotherapy for breast cancer, and the maintenance dose is important for clinical outcomes in breast cancer patients (9-11). However, older patients tend to have more underlying diseases and poorer physical tolerance. Compared to young breast cancer patients, elderly and frail patients are prone to increased chemotherapy toxicity, which can lead to drug dose reduction and treatment delays (12,13). Therefore, a reduction in the dose of chemotherapy or delaying the continuation of chemotherapy in NAT can lead to a decrease in antitumor efficacy and an increase in drug-resistant tumors (14,15). A study reveals that elderly breast cancer patients have the potential to delay the surgery after the completion of NAT due to poor tolerance compared to younger patients (16). Nevertheless, combining NAT with surgery has been reported to improve overall survival (OS) in older breast cancer patients if given the right candidate (17).

Locally advanced breast cancer in elderly patients is not a contraindication to mastectomy (18). Regardless of neoadjuvant or adjuvant therapy, surgical resection can improve OS in elderly patients (19). A survey showed that for elderly patients with large breast tumor, more experts would recommend immediate mastectomy (55%), while some would recommend neoadjuvant endocrine therapy followed by breast-conserving surgery (27%) (20). So, for locally advanced elderly breast cancer, upfront surgery is also a feasible method.

The timing of surgery for elderly patients with locally advanced breast cancer is controversial. Therefore, in this study, we selected locally advanced elderly breast cancer patients to further explore the effect of surgical sequence on survival. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-805/rc).

Methods

Data source and study population

Since the HER-2 data were only available after 2010 in the Surveillance, Epidemiology, and End Results (SEER) database, this study utilized data from 2010 through 2015. Women diagnosed with locally advanced non-metastatic breast cancer between 1 January 2010 and 31 December 2015 were identified in the SEER database. The SEER program’s registry consists of population-based cancer registries that cover approximately 28 percent of the US population.

Inclusion criteria for this study: (I) the gender was female; (II) age ≥70 years; (III) the primary site of the tumor was the breast; (IV) the diagnosis time was 2010–2015; (V) the patient undergoes surgical treatment; (VI) the tumor-node-metastasis (TNM) stage was T3-4N0-3M0. Exclusion criteria: (I) the diagnosis was only obtained from biopsy or autopsy; (II) patients for whom information about important demographic, clinical, pathological, and treatment variables was unknown; (III) patients with a history of other cancers.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The use of a public database by this study was considered exempt from institutional review board approval.

Statistical analysis

To evaluate the impact of surgical sequence on prognosis, the study cohort was divided into two groups based on treatment type: the upfront surgery group and the NAT group. Breast cancer-specific survival (BCSS) was defined as the time from the date of diagnosis to the date of death from breast cancer. OS was defined as the time from diagnosis to death for any cause or the last follow-up. Sociodemographic and clinical variables including age, marital status, race, grade, stage, T stage, N stage, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER-2) status, molecular subtype, and sequence of surgery were compared between the groups. Hormone receptor (HR) include ER and PR. Sociodemographic and clinical variables among breast cancer patients were assessed as categorical variables. The Pearson Chi-squared test was used to analyze the variables between the groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between locally advanced breast cancer and OS were estimated using Cox proportional hazards regression. Models were conducted among the general study population. The selection of variables in the multivariate regression model was based on the relationship between potential confounding factors and the OS rate. Then, multivariate Cox regression analysis was performed to find independent prognostic factors for elderly patients with locally advanced breast cancer (P<0.05).

The Kaplan-Meier curve and the log-rank test were used to calculate survival for surgical sequence decisions (upfront surgery versus NAT) in eligible patients. In the subgroup analysis of HER-2 positive and HER-2 negative breast cancer, the propensity score matching (PSM) was used to match the upfront surgery group and the NAT group to eliminate the baseline difference. The match ratio of patients in the upfront surgery and the NAT groups was 1:1 using the nearest-neighbor algorithm within a caliper of 0.01. The covariates used for matching included age, marital, race, grade, stage, T stage, N stage, ER status and PR status.

The P value of less than 0.05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS Statistics (version 22.0, IBMCorp., Armonk, NY, USA) and the R soft (version 4.0.3, R Foundation for Statistical Computing, Vienna, Austria).

Results

Description of the study population

The study included 2,191 older women with locally advanced breast cancer who underwent surgery between 2010 and 2015. Of all participants, 1,498 women (68.4%) received upfront surgery and 693 women (31.6%) received NAT. In the population treated with NAT, patients were younger and had a greater proportion of other races. The NAT group had a higher tumor grade, an advanced stage, a higher T and N stage, a higher rate of ER negativity, a higher rate of PR negativity, and a higher rate of HER-2 positivity. The NAT group had a greater proportion of HR−/HER-2+ and HR−/HER-2− (Table 1).

Survival and prognostic analysis of elderly patients with locally advanced breast cancer

The median follow-up for the study population was 50 months (range 0 to 107 months). Age, marital status, race, grade, stage, ER, PR, HER-2, and surgery sequence were included in multivariate Cox regression. The results showed that age, grade, stage, ER, and HER-2 were independent risk factors for the prognosis of OS and BCSS (P values were less than 0.05) (Table 2). But there was no statistically significant difference in the sequence of surgery, and it was not an independent prognostic factor for OS (P=0.72) and BCSS (P=0.94).

Survival analysis of surgical sequence elderly patients with locally advanced breast cancer

The 5-year OS and 5-year BCSS rates of the surgery group were 60.67% and 74.19%, respectively. The 5-year OS and 5-year BCSS rates of the NAT group were 59.74% and 71.34%, respectively. The Kaplan-Meier survival curve showed that there was no significant difference in OS between the surgery group and the NAT group (Figure 1A, P=0.92) and there was no significant difference in BCSS between the surgery group and the NAT group (Figure 1B, P=0.17). In the subgroup analysis, we found that in stage II and III breast cancer, the sequence of surgery did not affect the patient’s OS (Figure 2A,2B). Similarly, in the subgroup analysis of ER/PR subtypes breast cancer, there was no significant difference in the sequence of surgery for OS (P values were greater than 0.05) (Figure 3A-3D). However, for old patients with locally advanced HER-2 positive breast cancer, NAT can improve OS compared to upfront surgery (Figure 3E, P=0.001). For HER-2 negative breast cancer patients, upfront surgery compared to NAT can improve OS (Figure 3F, P=0.045).

Figure 1 Kaplan-Meier survival curves of overall survival and breast cancer-specific survival stratified by surgery and NAT. (A) OS; (B) BCSS. BCSS, breast cancer-specific survival; NAT, neoadjuvant therapy; OS, overall survival.

Figure 2 Kaplan-Meier survival curves of overall survival stratified by surgery and NAT in stage subgroups. (A) Stage II; (B) stage III. NAT, neoadjuvant therapy; OS, overall survival.

Figure 3 Kaplan-Meier survival curves of overall survival stratified by surgery and NAT in receptor status. (A) ER+; (B) ER−; (C) PR+; (D) PR−; (E) HER-2+; (F) HER-2−. ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; NAT, neoadjuvant therapy; OS, overall survival; PR, progesterone receptor.

To further confirm the results of surgical sequence in HER-2 positive patients and HER-2 negative patients, we performed PSM analysis. In the analysis of HER-2 positive patients, A total of 94 patients who received NAT were matched with 94 patients who had upfront surgery. After matching, there were no statistically significant differences between the two groups in age (P=0.86), marital status (P=0.84), race (P=0.51), grade (P=0.64), stage (P>0.99), T stage (P=0.88), N stage (P=0.99), ER status (P=0.75), and PR status (P>0.99) (Table 3). Similarly, in the analysis of HER-2 negative patients after matching, there were no statistically significant differences in clinicopathological features between the NAT and surgery group (Table S1). Kaplan-Meier survival analysis showed that NAT improved OS in locally advanced elderly patients with HER-2 positive in the post-match cohort (Figure 4A, P=0.03). There were no significant differences in survival between NAT and upfront surgery in locally advanced elderly patients with HER-2 negative in the post-match cohort (Figure 4B, P=0.83).

Figure 4 Kaplan-Meier survival curves of overall survival stratified by surgery and NAT in matched case-control analysis. (A) HER-2+; (B) HER-2−. HER-2, human epidermal growth factor receptor 2; NAT, neoadjuvant therapy; OS, overall survival.

Discussion

It should be noted that for Cox regression of OS and BCSS in locally advanced patients, our study showed that younger age, lower grade, lower stage, and positive ER decreased the survival risk of patients, which is consistent with the traditional risk of recurrence of St. Gallen. However, for elderly patients with locally advanced breast cancer, HER-2 positive is a better prognostic factor, which is inconsistent with conventional wisdom. HER-2 is a member of the HER family (EGFR/HER-1, HER-2, HER-3, HER-4) of the transmembrane receptor tyrosine kinase and is involved in cell proliferation, motility, anti-apoptotic, aggressive, and angiogenesis (21). In 1978, Slamon reported that HER-2 was amplified in 30% of invasive breast cancers and established a significant clinical correlation between HER-2 amplification/overexpression and adverse clinical outcomes (22). HER-2 positivity accounts for approximately 15 to 20% of breast cancers (23). A review indicated that the vast majority of studies have shown that overexpression of the HER-2 gene, message, or protein is a risk factor independent of other prognostic variables (24). Interestingly, with the development of targeted drugs, HER-2 positive breast cancers that originally had a poor prognosis can significantly improve the prognosis after receiving anti-HER-2 therapy.

The earliest and most important targeted therapy for breast cancer is anti-HER-2 therapy for HER-2 positive breast cancer. Trastuzumab is the first targeted drug for anti-HER-2 therapy in breast cancer. Its emergence is a milestone in the treatment of breast cancer. The analysis of NSABP B-31 & N9831 has confirmed the efficacy and safety of adding trastuzumab to adjuvant therapy for HER-2 positive breast cancer (25). In NAT for HER-2 positive breast cancer, trastuzumab anti-HER-2 therapy combined with chemotherapy significantly improved PCR compared to chemotherapy alone, making anti-HER-2 targeted therapy one of the standard treatment regimens for NAT for HER-2 positive breast cancer (4,5). With the development of anti-HER-2 drugs, PEONY trial randomized phase III trials have shown that trastuzumab plus pertuzumab can further improve PCR and 5-year disease-free survival rates for NAT compared to trastuzumab (26). Although trastuzumab is cardiotoxic and older patients often have some underlying heart disease, research indicates that its benefits outweigh risks even in patients over 70, given appropriate monitoring and management (27).

The biological behavior of elderly breast cancer is better. According to previous clinical trials, different subtypes of breast cancer have different responses to NAT. A meta-analysis of 20 clinical trials involving 8,095 breast cancer patients treated with neoadjuvant chemotherapy showed that the overall PCR rate was 18.5% (16.2–21.1%). The PCR rates of Luminal A, Luminal B, HER-2 positive and triple negative breast cancer subtypes were 8.3% (6.7–10.2%), 18.7% (15.0–23.1%), 38.9% (33.2–44.9%) and 31.1% (26.5–36.1%), respectively, suggesting that molecular subtypes are closely related to the PCR rate, and HER-2 positive and triple negative breast cancer subtypes have higher PCR rates (28).

Similarly, the multivariate Cox regression and Kaplan-Meier survival analysis indicate no statistical difference in survival based on surgical sequence in the general population. However, by our subgroup analysis, we found that NAT has a statistically better prognosis than the surgery group in patients with HER-2 positive (Figure 3E, P=0.001). In general, patients receiving NAT tend to have more aggressive tumors and higher stages. Similarly, our study showed that in elderly breast cancer patients, the group receiving NAT had a higher tumor grade and an advanced stage. After eliminating clinicopathological differences by PSM, our conclusion was again validated: in patients with HER-2 positive, NAT had a better prognosis than in the surgery group (P=0.03, Figure 4A). The main reason for this may be that the life expectancy of older breast cancer patients is low and although chemotherapy can improve the effectiveness of tumor treatment, the long-term side effects of chemotherapy may outweigh the benefits to the elderly. A systematic review of prospective randomized trials involving patients aged 60 and above showed that the elderly population treated with trastuzumab had a relative risk reduction of 47% compared to chemotherapy alone. This benefit was similar to that observed in younger patients (29). Chemotherapy toxicity increases in older women, resulting in dose reductions and treatment delays, compared to younger women (30). Similarly, a review had shown that the benefits of chemotherapy decreased as patients aged (31). However, the side effects of targeted therapy are relatively mild and will not cause serious systemic damage in elderly patients, so patients can complete targeted therapy with a complete course of treatment. A recent study has shown that elderly breast cancer patients receiving low relative dose intensity chemotherapy have poor survival outcomes. Therefore, before starting chemotherapy, elderly patients with a low risk of relative dose intensity should be identified, and targeted therapy should be performed (32).

The physical condition of the elderly plays an important role in the formulation of disease treatment plans. Frailty is defined as a decline in the body’s reserve capacity, making it vulnerable to external stress factors. For the elderly, in most clinical situations, weakness significantly increases the likelihood of adverse health consequences (33). The comprehensive geriatric assessment (CGA) is a systematic assessment method used to objectively evaluate the health status of the elderly, focusing on aspects such as physical, functional, and psychosocial. The value of CGA in geriatric medicine has been widely recognized (34). A review indicates that in elderly cancer patients, the CGA scores are related to chemotherapy toxicity and the completion rate of chemotherapy (35).

Our study suggests that NAT is a better treatment for locally advanced elderly breast cancer with HER-2 positive. However, the study also had the following limitations. First, the study was retrospective and had biases that could not be avoided by retrospective studies, such as selection bias. Second, the study did not provide important information such as neoadjuvant chemotherapy regimens, radiotherapy regimens, immunotherapy regimens, endocrinotherapy regimens, targeted treatment regimens, and patient adherence. Future prospective, multicenter studies are needed to further explore.

Conclusions

Age, grade, stage, ER, and HER-2 status are prognostic factors for locally advanced elderly breast cancer. For HER-2 positive elderly patients with locally advanced breast cancer, NAT can improve survival.

Acknowledgments

We would like to thank the Surveillance, Epidemiology, and End Results (SEER) program for their valuable data contribution to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-805/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-805/prf

Funding: This work was supported by the Wu Jieping Medical Foundation (No. 320.6750.2022-19-12).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-805/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 and its subsequent amendments.

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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