Sarcopenia Emerges as a Modifiable Prognostic Factor in Breast Cancer, Driving Calls for Standardized Screening and Multimodal Intervention
核心洞察
Sarcopenia (搜索) affects 12% to 49% of breast cancer (搜索) patients across perioperative and neoadjuvant settings, with prevalence varying by diagnostic criteria, ethnicity, and treatment exposure.
Low muscle mass independently predicts inferior overall survival, reduced pathological complete response rates, heightened chemotherapy toxicity, and increased postoperative complications.
Multimodal interventions combining resistance training, protein optimization, and nutritional support show preliminary efficacy in preserving lean mass and reducing treatment-related adverse effects.
Sarcopenia (搜索)—a progressive syndrome of skeletal muscle loss—has emerged as a critical, potentially modifiable host factor shaping treatment tolerance and long-term outcomes in breast cancer (搜索). Two comprehensive reviews published in Frontiers journals synthesize the growing body of evidence linking low muscle mass to inferior survival, heightened toxicity, and increased surgical morbidity, while also mapping emerging therapeutic strategies that could transform muscle health from a passive biomarker into an active target across the breast cancer care continuum.
The prevalence of sarcopenia (搜索) in breast cancer (搜索) populations is strikingly high, though estimates vary widely depending on diagnostic thresholds, imaging modalities, and clinical context. Wang and colleagues, writing in Frontiers in Cell and Developmental Biology, report that prevalence ranges from approximately 14% to over 55% across studies, with rates climbing to 41.6% in metastatic disease. Xiang and colleagues, in Frontiers in Surgery, document a similarly broad range of 12% to 49% across perioperative and neoadjuvant settings. Among 88 Japanese patients undergoing total mastectomy, sarcopenia was identified in 49% when assessed by psoas muscle index on preoperative CT. In a Western neoadjuvant chemotherapy cohort of 258 patients, the rate was 12.2%, while Korean cohorts have consistently reported higher baseline burdens, with one study finding sarcopenia in 25.2% of patients prior to treatment initiation.
Prognostic Implications Across the Care Continuum
The association between skeletal muscle depletion and adverse outcomes represents one of the most consistently replicated findings in breast cancer (搜索) research. Du and colleagues demonstrated that sarcopenic patients with early-stage breast cancer exhibited significantly reduced overall survival rates at one year (82.94% versus 85.78%), three years (81.76% versus 83.91%), and five years (80.59% versus 81.17%) compared with non-sarcopenic counterparts. Huh and colleagues showed that low total abdominal muscle area measured on preoperative PET-CT was a strong independent prognostic biomarker for overall survival, with an even more pronounced effect in patients aged 50 years or older.
In the neoadjuvant setting, sarcopenia (搜索) has been linked to reduced pathological complete response (pCR) rates. Günaltılı and colleagues analyzed 85 patients with HER2-positive or triple-negative breast cancer (搜索) and identified low skeletal muscle index as the sole independent predictor of pCR on multivariate logistic regression; patients without low SMI had four-fold higher odds of achieving pCR. Isıklar and colleagues reported that non-sarcopenic patients achieved a 62.5% pCR rate compared with 37.5% in sarcopenic individuals.
The integration of muscle metrics with systemic inflammatory indices further amplifies prognostic discrimination. Tang and colleagues demonstrated that the concomitant presence of adverse muscle and inflammatory profiles conferred a multiplicative risk for poor five-year overall survival (HR 16.36; P = 0.016) compared with either parameter alone in patients with lymph node-positive breast cancer (搜索) after radical mastectomy.
Treatment Toxicity and Surgical Complications
Sarcopenia (搜索) erodes physiological reserve, predisposing patients to heightened treatment-related toxicity. Meta-analytic evidence consistently confirms that baseline sarcopenia is a robust predictor of grade 3 or higher chemotherapy toxicity, dose reductions, hospitalization, and treatment discontinuation across both early and metastatic stages. Shachar and colleagues demonstrated that reduced baseline skeletal muscle index and skeletal muscle density were significantly associated with grade 3–4 chemotherapy toxicities, including hematological and gastrointestinal events, in patients treated with anthracycline and cyclophosphamide followed by taxane-based chemotherapy.
In the surgical domain, sarcopenia (搜索)'s predictive value appears context-dependent. Pittelkow and colleagues reported that sarcopenic patients undergoing autologous microsurgical breast reconstruction experienced significantly higher rates of flap-site delayed healing (37.5% versus 20.0%; P = 0.046), unplanned return to the operating room (25% versus 11.6%; P = 0.05), and prolonged ICU and hospital length of stay. However, Broyles and colleagues found no association between sarcopenia and complications in abdominally based free-flap reconstruction, and Aleixo and colleagues similarly reported no correlation in a cohort of 682 patients with stage I–III breast cancer (搜索), identifying obesity as the dominant risk factor.
Mechanistic Pathways
Several biological pathways may mediate the relationship between sarcopenia (搜索) and adverse breast cancer (搜索) outcomes. Wang and colleagues detail pharmacokinetic alterations, noting that low muscle mass is associated with a reduced volume of distribution for chemotherapeutic agents, resulting in elevated drug concentrations and increased toxicity risk. Hertz and colleagues found that paclitaxel volume of distribution was significantly correlated with skeletal muscle area at the thoracic level, and that prolonging infusion time helped mitigate peripheral neuropathy risk.
Myokine dysregulation and chronic inflammation represent another key axis. Sarcopenic patients exhibit elevated markers of inflammatory response, and chronic inflammation promotes tumor progression while simultaneously inducing protein catabolism that further exacerbates muscle loss. Insulin resistance, commonly accompanying sarcopenia (搜索), may activate the PI3K/AKT/mTOR pathway, enhancing breast cancer (搜索) cell proliferation and invasive potential.
Emerging Therapeutic Strategies
Multimodal interventions centered on resistance training, protein optimization, and oral nutritional support show preliminary efficacy. A meta-analysis of 59 randomized controlled trials demonstrated that sarcopenia (搜索) interventions yield statistically significant improvements in muscle mass, muscle strength, and select measures of physical performance, with multi-component approaches conferring the greatest benefit. In early-stage breast cancer (搜索), a multicenter randomized controlled trial demonstrated that resistance exercise training effectively reversed sarcopenia and improved quality of life and fatigue, while aerobic exercise training was more advantageous in reducing body fat.
On the pharmacological front, the GDF-15 (搜索)–GFRAL axis has emerged as a tractable target. The anti-GDF-15 antibody ponsegromab increased body weight, appetite, muscle mass, and physical activity in cachectic patients in a Phase 2 trial. Preclinical studies demonstrate that combining anti-myostatin (搜索) and anti-GDF-15 antibodies produces synergistic gains in body weight and hindlimb muscle mass. Repurposed agents including pindolol, a non-selective β-adrenergic receptor antagonist, and sulfasalazine, an anti-inflammatory agent, have shown promise in preclinical models by reducing systemic inflammation and preserving skeletal muscle.
Selective androgen receptor modulators such as enobosarm have demonstrated significant increases in lean body mass in patients with cancer-induced muscle wasting, though morphological gains have rarely translated into statistically significant improvements in physical performance. Bimagrumab, a monoclonal antibody targeting the activin type II receptor, has elicited profound hypertrophic responses while simultaneously reducing adipose tissue mass—a dual-action profile particularly relevant to the sarcopenic obesity phenotype frequently observed following breast cancer (搜索) chemotherapy and endocrine therapy.
The Path Forward
Despite growing recognition, diagnostic heterogeneity remains a critical barrier. The European Working Group on Sarcopenia (搜索) in Older People (EWGSOP2), the Global Leadership Initiative in Sarcopenia (GLIS), and the Asian Working Group for Sarcopenia (AWGS) 2025 consensus employ differing criteria, and CT-based skeletal muscle index thresholds vary considerably across studies. Both reviews call for standardized, setting-specific surveillance protocols and breast cancer (搜索)-specific randomized trials to define optimal timing, intensity, and composition of exercise-nutrition prehabilitation.
Ongoing clinical trials, including a study evaluating resistance exercise intervention for sarcopenia (搜索) in breast cancer (搜索) patients undergoing neoadjuvant chemotherapy (KCT0008961) and a trial investigating sarcopenia as a predictor of treatment-related toxicity (NCT06274268), may provide higher-level evidence. The ultimate goal, both reviews conclude, is to incorporate comprehensive sarcopenia management into the holistic treatment framework for breast cancer, elevating muscle health from an observational prognostic biomarker to a genuinely modifiable therapeutic target.