Impact of gene polymorphism on toxicity and clinical outcome in breast cancer patients treated with doxorubicin, cyclophosphamide and taxane-based chemotherapy

Abstract

Background: Women with breast cancer receiving doxorubicin, cyclophosphamide, and taxane-based (AC-T) chemotherapy show considerable differences in both clinical response and toxicity, and clinical factors alone do not fully explain this variation. Genetic differences in drug transport and metabolism may contribute, yet data from South Asian populations, including Bangladesh, are limited. This study focuses on SLCO1B3 rs4149117, ABCB1 (rs2032582, rs1128503, rs3213619, rs1045642), ABCC2 rs17222723, and CYP2C8 rs11572080 variants and their association with breast cancer risk, response to therapy, and AC-T-related toxicities in women with breast cancer in Bangladesh. Methods: A total of 249 patients receiving doxorubicin, cyclophosphamide, and subsequently either paclitaxel or docetaxel, along with 251 controls, were included. Clinical information and toxicity outcomes were obtained from interviews and medical records. Genotyping was carried out using tetra-primer ARMS-PCR for rs4149117, whereas PCR-RFLP was used for rs2032582, rs1128503, rs3213619, rs1045642, rs17222723, and rs11572080. Tumor response was evaluated following RECIST v1.1, and treatment-related toxicities were graded according to CTCAE v5.0. Results: Patients who were underweight or had triple-negative tumors tended to respond poorly to AC-paclitaxel, whereas patients diagnosed with infiltrating or metastatic ductal carcinoma demonstrated a more favorable response to AC-paclitaxel. Dysgeusia (78.71%) was the most common non-hematological toxicity, anemia (61.45%) was the most common hematological toxicity, and hepatotoxicity (30.92%) was the most common organ toxicity. Furthermore, 10.84% died within 5 years of their cancer diagnosis, 7.23% died after 5 years of diagnosis, and 81.93% were still living at the time of our last follow-up. SLCO1B3 rs4149117 showed a consistent protective association with breast cancer. Whereas ABCB1 rs1128503 and ABCB1 rs1045642 exhibited an elevated risk for breast cancer, along with poorer responses to AC-paclitaxel. In addition, ABCB1 rs2032582, ABCB1 rs3213619, ABCC2 rs17222723, and CYP2C8 rs11572080 variants showed no risk associations and were not associated with treatment response. Distinct genotype-toxicity patterns emerged during AC-paclitaxel therapy, and no meaningful associations were observed with AC-docetaxel. Conclusion: These findings suggest a potential role for pharmacogenetic markers and support more personalized approaches for breast cancer patients in South Asia, including Bangladesh