Assessment of the toxicity profile and safety of integrating metformin into neoadjuvant chemotherapy for breast cancer

Avierin D.1, Zavizion V.2

Summary. Introduction. The department of oncology and medical radiology at Dnipro state medical university is studying the effects of metformin on systemic breast cancer treatment, particularly its ability to modify the cytostatic effects of chemotherapeutic agents and reduce their side effects. Metformin regulates tumor cell proliferation and reduces resistance, impacting various body systems including anti-inflammatory and immunomodulatory properties, though it may cause gastrointestinal and hematological side effects. Its integration into neoadjuvant therapy significantly increases the complete pathological response rate from 12% to 27% (p <0.001), highlighting its potential to improve therapeutic outcomes. Studying its toxicity profile with chemotherapeutic drugs is critically important for further research on metformin in oncology. Objective. The study aimed to investigate the clinical toxicity profile and safety of integrating metformin into neoadjuvant chemotherapy for breast cancer. Materials and methods. Side effects of using metformin in combination with neoadjuvant chemotherapy were considered in 128 patients with stage I–III breast cancer. The average age of the patients was 51,86 years (95% confidence interval (CI) from 49,73 to 53,99). The study focused on the per-course monitoring of adverse events, grading them, and examining the interrelationships. Patients were randomized into three groups: the first was the control group receiving standard treatment, the second was experimental combining standard treatment with 500 mg of metformin three times a day, and the third was experimental combining standard treatment with 850 mg of metformin twice a day. Results. The study analyzed common complications of breast cancer chemotherapy, such as neutropenia, diarrhea, neuropathy, and general weakness. The severity of symptoms was assessed according to NCI CTCAE v5.0. Main methods for controlling neutropenia included weekly clinical blood analysis evaluations. It was found that the average degree of neutropenia varied from mild to moderate depending on the course and group, but the overall impact of metformin on the development of severe neutropenia was statistically insignificant (p >0.05), with a general tendency to reduce the average degree of this complication with each subsequent treatment course (p <0.001). Diarrhea assessment showed that the relationship between metformin dosage and the development of diarrhea was statistically significant only in the first course (p <0.05), with no significant connections in subsequent courses. A two-factor ANOVA found no statistically significant effect of treatment protocols and metformin dosage on the development or severity of diarrhea (p >0.05). Also, an analysis of the relationship between the course of treatment and the degree of polyneuropathy found a moderate correlation, confirming an increased risk of polyneuropathy with the number of courses of treatment (p <0.001). However, changes in the degrees of neutropenia, diarrhea, and polyneuropathy were not significantly associated with different metformin dosages. Conclusions. The study confirms the importance of monitoring hematological parameters and the potentially useful role of metformin in reducing certain chemotherapeutic complications, although its impact on more severe stages, such as neutropenia, was limited. The inclusion of metformin in clinical protocols can be considered a strategic step to improve treatment outcomes, but the final decision should be based on an individual analysis of each clinical case and additional data from other studies.

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