In this study, we enrolled and analyzed the relationship between preoperative FFA levels and outcomes in 4133 breast cancer patients. We found that lower preoperative serum FFA level was significantly associated with worse OS in breast cancer. FFA exhibited a nonlinear U-shaped curve correlation with the survival in BC patients. Compared to patients with high FFA levels (250–715µmol/L), patients with low FFA levels (≤ 250µmol/L) had significantly higher rates of all-cause mortality and cancer-specific mortality in total population and those with a normal BMI.
Breast cancer is the most common malignancies in Chinese women and seriously impairs patients' physical and mental health (Fan et al. 2014; Li et al. 2020). In addition to well-characterized genetic influences, several environmental risk factors such as dietary habits and obesity have a significant influence on development and progression of breast cancer (Blucher et al. 2017; Karmokar et al. 2022). FFA, an energy-generating nutrient, serves as signaling molecules in various cellular process (Al et al. 2022; Lymperopoulos et al. 2022). Furthermore, as a metabolite substrate, FFA is involved in epigenetic regulation of tumor occurrence and progression through histone acetylation, malondialdehyde, butylation and palmitoylation (Currie et al. 2013; Jiang et al. 2022; Martin-Perez et al. 2022; Sabari et al. 2017; Zhang et al. 2021). A retrospective study of 2206 patients has indicated that abnormal serum FFA levels were associated with an increased risk of cancer, especially lung cancer, gastric cancer, thyroid cancer, rectal cancer, colon cancer, and ovarian cancer, but not breast cancer (Zhang et al. 2020b). Several epidemiological and experimental studies have reported that FFAs are important factors in breast cancer risk (MacLennan et al. 2010; Madak-Erdogan et al. 2019a). The curve relationship between FFA and the prognosis of BC remain largely unclear. Therefore, we analyzed the clinical data of breast cancer patients, finding that the serum preoperative FFA had a U-shaped curve correlation with OS in BC patients and lower preoperative serum FFA levels were associated with worse OS in BC.
Previous studies have shown that elevated plasma free fatty acid levels are associated with an increased risk of breast cancer in obese patients (Madak-Erdogan et al. 2019b). Obesity is closely related to the level of free fatty acids (Boden 2008b). Therefore, we aimed to explore the relationship between preoperative serum FFA levels and breast cancer OS in different BMI subgroups. The results showed that in the population with normal BMI (18.5–24.9 kg/m2), patients with low levels of free fatty acids had worse OS in breast cancer. But no similar effect was observed in the other BMI subgroups. The probable explanation was that compared with other subgroups, patients with normal BMI accounted for the majority of the population in our research. Thus, the association between FFA and OS in BC could not be better analyzed due to insufficient data for other BMI subgroups. What’s more, in the population with normal BMI (18.5–24.9 kg/m2), we found that the association between serum FFA levels and the OS presented a nonlinear U-shaped curve. Patients with lower levels of free fatty acids (≤ 250µmol/L)had worse OS in breast cancer. Although those with high free fatty acids (≥ 715µmol/L) also had worse outcomes, no statistical significance was observed. One possible reason for this that there are relatively few patients with high levels of free fatty acids in normal BMI group.
The pathogenetic mechanisms underlying the association between low preoperative serum FFA levels and adverse outcomes remain unknown. A recent study by Ying Pan et al. demonstrated that low FFA levels were associated with a higher risk of mortality in coronary artery disease patients with type 2 diabetes mellitus (T2DM) (Pan et al. 2023). Furthermore, Kathryn Moore et al. indicated that myocardial infarction (MI) accelerated breast cancer outgrowth and cancer-specific mortality both in mice and humans (Koelwyn et al. 2020). Thus, it is still unclear whether the physiological deficiency of FFA affects insufficient energy supply to the heart itself, which exacerbates the occurrence of long-term adverse cardiovascular events and in turn may lead to unfavorable prognosis in breast cancer patients.
FFAs, as critical energy sources, mainly play a pivotal role in lipid metabolism and can be metabolized through β-oxidation in the mitochondrial matrix (Adeva-Andany et al. 2019). Due to chronic restriction of dietary energy intake suppressing FFA levels (Henderson 2021) and affecting the proliferation of hematopoietic stem cells (HSCs) (Mistry et al. 2021) and the function of CD8+T cell (Ringel et al. 2020), another explanation may lead to a nonlinear U-shaped curve with increased mortality at lower FFA levels.
Nevertheless, the current study has certain limitations. First, the analysis was performed in the Southern China population and the results of this study did not necessarily apply to Northern China population or other ethnic groups. In addition, a multicenter large sample cohort study is needed to verify the reliability of the conclusion. Second, we only collected the preoperative FFA level, and we did not analyze the dynamics of total FFA and FFA subclasses over the duration of the study. Our failed to assess all metabolic factors and parameters in patients with breast cancer, including insulin resistance, diet, inflammation and other confounding factors, which may help reveal the possible mechanism of action between FFA levels and OS in BC patients. Finally, it is important to note that the exact cutoff values used to define FFA may vary depending on the study population and the FFA measurement method.