Sarcopenia’s Role in Neoadjuvant Chemotherapy Outcomes for Locally Advanced Breast Cancer: A Retrospective Analysis

Introduction

Breast cancer continues to be the most common type of malignancy among women, accounting for 15% of cancer deaths [1,2]. The enhanced focus on early diagnosis and the development of more efficacious therapies has led to a reduction in the mortality associated with breast cancer, but quality of life can be adversely affected [3]. Over time, quality of life has become an important outcome measure in clinical research and survival studies for breast cancer, due to advancements in diagnosis and treatment of the disease [4].

Sarcopenia, originally defined by Rosenberg in 1989 as “muscle loss”, involves a reduction in skeletal muscle mass [5]. Since this primitive initial definition, sarcopenia has evolved beyond mere muscle loss. Today, sarcopenia is recognized as a geriatric syndrome characterized by muscle insufficiency; it presents as decreased muscle mass, function, and performance [6]. The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) defines sarcopenia as a “progressive and generalized skeletal muscle disorder associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and death” [5,7]. Decreased muscle strength, low muscle quality, and reduced physical performance are accepted diagnostic criteria by EWGSOP2, and sarcopenia is considered severe when all 3 criteria are met [7].

While sarcopenia plays a significant role in the progression of chronic illness, symptoms like physical inactivity and loss of appetite can in turn exacerbate sarcopenia [8]. Patients with sarcopenia have lower tolerance to cancer treatments; they are more susceptible to complications such as infections, chemotherapy toxicity, and perioperative problems, all of which complicate cancer treatment [7,9]. There are 4 main reasons for sarcopenia during chemotherapy: (I) reduced intake of vitamin D, omega-3 fatty acids, and protein due to impaired food intake; (II) decreased physical activity due to fatigue; (III) the direct effect of chemotherapy or targeted agents on muscle; (IV) malabsorption due to mucositis or treatment-related pancreatic insufficiency [10].

Some studies have shown that pre-treatment sarcopenia predicts chemotherapy toxicity, reduced treatment response, increased disability, poor anti-tumor response, and lower survival rates [11]. Sarcopenia is linked to increased dose-limiting toxicities in patients undergoing chemotherapy for breast cancer [12]. Early-stage breast cancer patients on adjuvant chemotherapy have a high risk of sarcopenia [13]. The relationship between breast cancer and sarcopenia has been studied in early-stage and metastatic breast cancer [14]; however, it has not been sufficiently investigated in locally advanced breast cancer patients receiving neoadjuvant therapy. The limited data in the literature are based on studies with relatively small sample sizes [15,16]. Therefore, the present retrospective study, which included 226 women with locally advanced breast cancer, aimed to evaluate the association between sarcopenia, measured by right and left psoas muscle area (PMA), and outcomes before and after neoadjuvant chemotherapy (NAC).

Material and Methods

ETHICAL STATEMENT:

This retrospective cohort study was conducted according to the standards of the Helsinki Declaration and approval was obtained from the Health Sciences University Antalya Training and Research Hospital’s clinical research ethics committee on 29.09.2022, with decision number 18/15.

STUDY DESIGN:

This retrospective cohort study included patients diagnosed with invasive breast cancer who received NAC at the Health Sciences University Antalya Training and Research Hospital between 2015 and 2021.

PATIENT SELECTION:

Patients with histologically confirmed stage II or III breast cancer, who underwent surgery after NAC and had complete follow-up data, were included. Early-stage or metastatic breast cancer cases and those with incomplete data were excluded. Demographic, clinicopathologic, and laboratory data were collected from archival files and the hospital database. Postoperative pathology reports were reviewed to document the pathologic response to NAC.

MEASUREMENTS:

For sarcopenia assessment, PMA measurements were obtained from routine computed tomography scans, as shown in Figure 1. The mean PMA was calculated by averaging the right and left psoas areas, and the 25th percentile (415.4 mm2) was used as the cut-off for sarcopenia, in accordance with previous studies [17–19]]. Tumor subtypes were categorized into human epidermal growth factor 2 (HER2)-positive, triple-negative, luminal A, and luminal B, based on immunohistochemical markers. Body mass index (BMI) was used to classify patients as overweight (BMI 25–29.9) or obese (BMI ≥30). Neoadjuvant chemotherapy regimens were in accordance with international guidelines, with anthracycline-cyclophosphamide followed by paclitaxel or docetaxel as the most common, and trastuzumab/pertuzumab added for HER2-positive cases.

Pathological complete response (pCR) was defined as the absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0). Response was graded using the Miller-Payne (MP) system [20]. Disease-free survival (DFS) was calculated from surgery to relapse, metastasis, or death, while overall survival (OS) was measured from diagnosis to death from any cause.

STATISTICAL ANALYSIS:

In our study, patients’right and left PMA values were measured before and after NAC. The pre-chemotherapy right and left measurements were summed and divided by 2 to obtain the average PMA value. The 25^th percentile of this value was found to be 415.4 mm², which was taken as the cut-off point. Sarcopenia presence before and after NAC was assessed based on the average of the right and left values, with individuals falling below the cut-off considered sarcopenic, while others were classified as normal. Statistical analyses were performed using the SPSS 29.0 software package. A P-value of less than 0.05 was considered statistically significant. Descriptive analyses of variables were conducted, with categorical variables presented as numbers and percentages, and continuous variables as means, standard deviations, medians, and 25^th–75^th percentiles. Chi-square and Fisher’s exact tests were used for the analysis of independent categorical variables, while the McNemar test was employed for dependent categorical variables. For survival analyses, the Kaplan-Meier method and log-rank test were applied, and results were presented as survival curves.

Results

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS:

The study included 226 female patients with a mean age of 50.0±11.5 years. Of these, 55.8% were postmenopausal, and 72.6% were either overweight or obese. A total of 32.7% of patients had at least one comorbid condition, with hypertension being the most common (22.1%), followed by diabetes (13.3%). Most patients were clinical stage II (58.8%) and had clinical N1 status (67.3%). Luminal B was the most prevalent subtype of breast cancer, with 64.6% being HER2 negative. The pathologic characteristics of the patients are summarized in Table 1.

NEOADJUVANT CHEMOTHERAPY RESPONSE:

The response to NAC revealed that 58.8% of patients did not achieve a pCR, and 41.1% were classified as MP-5 according to the MP grading system. During a median follow-up of 37.2 months, 8.8% of patients experienced disease recurrence, and 3.5% (8 patients) died (Table 2).

SARCOPENIA PREVALENCE:

The mean pre-NAC PMA was 502.8±118.0 mm2, decreasing to 454.3±115.1 mm2 post-NAC. Pre-NAC sarcopenia was present in 24.8% of patients, increasing to 40.7% after NAC. A total of 45 patients who were non-sarcopenic before NAC developed sarcopenia after undergoing NAC, while 9 patients with pre-NAC sarcopenia were no longer sarcopenic after receiving NAC. This increase in sarcopenic patients was statistically significant (P<0.001). The details are presented in Table 3.

ASSOCIATION WITH OBESITY:

Obesity was significantly associated with sarcopenia. Before NAC, 55.3% of non-sarcopenic patients were obese, and among the patients who were sarcopenic before receiving NAC, 100% were obese (P<0.001). Post-NAC, 43.3% of non-sarcopenic patients were obese, compared with 100% of sarcopenic patients (P<0.001).

PATHOLOGICAL CHARACTERISTICS:

No significant correlation was found between pre-NAC sarcopenia and the patients’ pathological characteristics. However, estrogen receptor positivity was observed in 75.4% of patients without sarcopenia and 62% of sarcopenic patients (P=0.031). Similarly, progesterone receptor positivity was higher in non-sarcopenic patients (62.7%) compared with sarcopenic patients (47.8%) (P=0.027). No significant associations were found between post-NAC sarcopenia and other pathological characteristics (Table 4).

IMPACT ON TREATMENT RESPONSE:

Pre-NAC sarcopenia did not influence the pathological response to treatment. Furthermore, no correlation was identified between sarcopenia and recurrence or mortality. Post-NAC sarcopenia was not associated with pCR, pathologic response, recurrence, or mortality (Table 5). In comparisons between pre- and post-NAC sarcopenia, no significant differences were observed in terms of pCR, recurrence, or mortality. Among patients without pre-NAC sarcopenia, 58.4% did not achieve pCR, and all patients without post-NAC sarcopenia also had a non-pCR response (P=0.012) (Table 6).

There were no significant differences in hematologic adverse effects between sarcopenic and non-sarcopenic patients, but patients with at least one comorbid condition showed significant differences in hematologic adverse effects (Table 7).

SURVIVAL ANALYSIS:

Survival analyses showed no statistical differences in DFS or OS between pre- and post-NAC sarcopenic and non-sarcopenic patients. The mean DFS for patients with pre-NAC sarcopenia was 6.27 years (95% CI 5.4–6.9), compared with 7.2 years (95% CI 6.7–7.7) for patients who developed sarcopenia post-NAC (P=0.111). The mean OS was 6.9 years (95% CI 6.3–7.5) for patients with pre-NAC sarcopenia and 7.1 years (95% CI 6.3–7.9) for those with post-NAC sarcopenia (P=0.547) (Figures 2, 3).

Discussion

The present study aimed to evaluate the impact of sarcopenia on treatment outcomes, pathological response, and survival in patients with locally advanced breast cancer undergoing NAC. Our findings suggest that sarcopenia, particularly post-treatment sarcopenia, is significantly associated with obesity but does not directly affect pathological response, recurrence, or OS.

Sarcopenia is associated with increased chemotherapy toxicity, heightened post-surgical complications, and reduced survival rates in oncological treatment regimens [21]. Sarcopenia is common in patients with breast cancer [22] and is associated with increased chemotherapy toxicity [23,24], earlier tumor progression [25], and a rise in overall mortality [26]. Therefore, sarcopenia should be assessed before starting cancer treatment in all patients to optimize treatment efficacy and tolerance and minimize adverse effects. While there is growing interest in the effects of sarcopenia on breast cancer, current literature primarily focuses on survival analyses, with limited studies examining the relationship between NAC and sarcopenia, particularly its impact on treatment toxicity. Our study aims to illuminate an underexplored area by examining the effects of sarcopenia on treatment response, toxicity, and survival in breast cancer patients receiving NAC.

In line with the literature, significant differences were found between median pre-NAC PMA values and post-NAC PMA values. Our study did not find a statistical relationship between pre-NAC and post-NAC sarcopenia and pCR, which is the most important indicator of response to NAC. However, we found that sarcopenia was statistically significantly higher in patients with a BMI of 30 or above both before and after NAC, and this situation became more pronounced in the post-NAC period. Another finding was that DFS and OS were not affected by the sarcopenic state.

The mean age of the 226 patients studied in our research aligns with existing literature [27–29], though our postmenopausal patient ratio was higher than reported rates. Direct comparison with the literature was not feasible due to different cut-off values in BMI classification. Similar to other studies evaluating neoadjuvant treatment [15,27–29], the use of anthracycline- and taxane-based regimens was prominent in our study.

Consistent with previous studies [30,31], a significant difference was found between the median pre- and post-NAC PMA values in our study. The increased number of sarcopenic patients following NAC underscores the importance of proper nutritional support during chemotherapy. Moreover, an increased incidence of post-NAC sarcopenia has been observed in patients with a BMI over 30 in line with a study by Iwase et al [15]. Consistent with previous studies [27,32], no significant relationship was found between sarcopenia and breast cancer subtypes or clinical stages.

Achieving a pCR following NAC is known as a proven prognostic factor. The few studies in the literature investigating the relationship between body composition changes or sarcopenia and obtaining pCR following NAC have conflicting results. In older studies evaluating only BMI, a high BMI was inversely correlated with pCR [16,33], while a meta-analysis of 8 major studies found no association between obesity and NAC response [34]. Despite conflicting results in studies using skeletal muscle area or muscle index measurements instead of BMI [27–29], our study did not show a significant association between pCR and pre- and post-NAC sarcopenia.

In our subgroup analyses, none of the 9 patients who improved from pre-NAC sarcopenia to post-NAC non-sarcopenia achieved pCR, showing statistical significance when compared with 125 patients who were non-sarcopenic both before and after NAC. Of the 56 patients with pre-NAC sarcopenia, those who improved post-NAC (9 patients) were statistically less responsive to NAC compared with the remaining 47 with persistent sarcopenia. This suggests a lower tendency of patients with resolved sarcopenia post-NAC to achieve pCR, indicating the need for larger, prospective studies.

The relationship between sarcopenia and chemotherapy toxicity represents a significant research area in the management of side effect profiles of oncological treatments, with growing evidence on the effects of sarcopenia [35]. The potential modulatory effect of sarcopenia on chemotherapy-induced toxicity, particularly in the context of NAC, was a primary research question of the present study. In the relevant literature, Prado et al’s study on metastatic patients undergoing capecitabine treatment found that severe toxicity incidents were twice as common in patients diagnosed with sarcopenia vs those without sarcopenia [25]. In patients without sarcopenia, this rate was only 20%. Similarly, another study on breast cancer patients undergoing adjuvant therapy found that individuals with higher lean body mass experienced less toxicity from epirubicin [25], further clarifying the relationship between sarcopenia and treatment adverse effects. Although limited in number, current studies specific to neoadjuvant treatment indicate a relationship between alterations in body composition and increased toxicity risk [24,36]. Although the hematologic adverse effects in our study were not in line with the literature, the aforementioned studies used different body composition measurement methods as well as different cut-off values. More importantly, significantly higher rates of hematologic toxicity were found in patients with at least one comorbidity, both pre- and post-NAC, who were sarcopenic. This is a standout finding in the current literature evaluating the sarcopenia-chemotherapy toxicity relationship, and represents a notable distinction between the present study and previous studies. These data emphasize the need to better understand the role of sarcopenia in treatment planning and side effect management strategies, particularly in breast cancer patients receiving NAC. These findings also indicate the potential of incorporating individual body composition into oncological treatment protocols to reduce adverse effects and improve treatment adherence.

The final evaluation in our study focused on survival. Studies in the literature have reported that sarcopenia may be a prognostic factor for survival in various types of cancer [24,26,37]. However, one study also indicated that it may not be a negative prognostic factor in patients with muscle-invasive bladder cancer [38]. In the study by Iwase et al, which assessed patients with locally advanced breast cancer undergoing NAC, no relationship was found between BMI or body composition measurements and OS [15]. In their study involving patients receiving NAC, Omarini et al also found that BMI or body composition parameters did not significantly affect OS and DFS [29]. Consistent with these 2 studies, our study also did not find a statistically significant relationship between survival parameters and sarcopenia.

A limitation of our study is the lack of a control group, which could have provided a more robust comparison of sarcopenia’s impact in a broader population. Furthermore, while we used PMA as a surrogate for sarcopenia, a more comprehensive volumetric analysis could provide deeper insights into muscle mass changes. Nonetheless, the use of PMA is validated as a reliable method for assessing sarcopenia in oncology, particularly in resource-constrained settings where volumetric measurements may not be feasible.

Conclusions

In conclusion, the present study highlights the complex relationship between sarcopenia, obesity, and treatment outcomes in breast cancer patients undergoing NAC. While sarcopenia increases significantly following NAC, it does not appear to affect pathological response or survival outcomes. Future research should focus on understanding the interplay between sarcopenia, obesity, and other comorbid conditions to better predict which patients may benefit from targeted interventions aimed at preserving muscle mass during cancer treatment.