Abstract P6-11-06: Capecitabine, eribulin and paclitaxel differentially impact the metabolite pool in metastatic breast cancer patients
Authors: Gandhi Shipra , Roy Arya Mariam , Takabe Kazuaki , Rosario Spencer 
Published: March 2023

Introduction: Metabolic reprogramming is recognized as a hallmark of malignancy. Cancer growth, and progression has been associated with lipid and amino acid absorption by cancer cells. However, the differential impact of chemotherapeutic agents on energy balance and metabolism while on-treatment and at the time of clinical progression, in breast cancer patients, is largely unknown. We hypothesize that increases in lipid and other related metabolites, like amino acids, throughout chemotherapy treatment are therapy-specific, and associated with disease progression. Methods: Serum samples from 15 metastatic breast cancer patients (hormone-receptor positive and triple negative breast cancer), receiving different chemotherapy regimens (n=5 paclitaxel, n=5 eribulin, n=5 capecitabine), were collected at multiple time points (baseline, 3- week on-treatment and disease progression). Disease progression was determined by CT scans using RECIST v1.1 criteria. Samples were prepared for metabolomics and analyzed via mass spectrometry using the MxP Quant 500 kit (Biocrates Life Sciences AG, Innsbruck, Austria). Data was processed using MetIDQ software (Biocrates Life Sciences AG). Limma was used to identify differential metabolites during treatment and at the time of disease progression as compared to metabolites at baseline. Results: With capecitabine treatment, there was a differential impact on many lipid metabolites, including ceramides, with an initial decrease on treatment: Cer(d18:2/18:1)(-1.95 log-fold change (logFC)); and arachidonic acid, (-1.32 logFC) (p&lt; 0.05 for both). However, at the time of disease progression, there was a 1.8 to 2 log-fold increase in Cer (d18:0/20:0); Cer (d18:1/22:0); Cer (d18:2/22:0); Cer (d18:1/23:0); 1.7 log-fold increase in diacylglycerol (DG (16:0_20:0)) along with 1.6 log-fold increase in amino acid methionine (p &lt; 0.05 for all). Conversely, in the eribulin group, while on treatment, there was a 1.2 to 1.3 log-fold increase in triglycerides (TG), i.e., TG(16:1_36:2); TG(16:0_36:2); TG(18:1_33:1); TG(16:1_36:1); TG(20:4_34:1) and 1.5 log-fold increase in amino acid kynurenine; while there was a 1.3 to 1.4 log-fold decrease in fatty acids (FA), such as FA(20:2); FA(18:2); FA(18:1) (p &lt; 0.05 for all). At the time of disease progression, there was a 1.2 to 1.3 log-fold decrease in lipids like cholesteryl esters (CE) and phosphatidylcholines (PC), e.g. CE (18:2); CE (18:3); PC aa 36:3; PC aa 36:2 (p &lt; 0.05 for all). Similarly, in the paclitaxel group, with treatment, there was a 1.2 to 1.8 log-fold increase in CE(22:0); Hex2Cer(d18:1/26:1) and DG(18:3_20:2) (p &lt; 0.05 for all), while, at the time of disease progression, there was a 2 log fold decrease in PC like lyso PC a C20:3; and lyso PC a C16:1, as well as 2 to 2.5 log-fold decrease in amino acids like glutamine, and sarcosine (p &lt; 0.05 for all). Conclusion: Lipid and amino acid pool while on treatment and at disease progression were differentially impacted by the three classes of chemotherapies, some of which to the same functional extent. Although a decrease in lipid metabolites was observed while on capecitabine (prodrug of 5-fluorouracil) treatment, an increase in both lipid metabolites and amino acids was observed at disease progression. With both paclitaxel and eribulin treatment, which are microtubule inhibitors, a decrease in lipid metabolites and amino acids was observed at disease progression. An understanding of differential metabolic reprogramming with different chemotherapeutic agents may provide novel points of therapeutic intervention for anti-cancer treatment, such as combination of chemotherapy with inhibitors of ceramide metabolism or amino acid inhibitors and contribute towards efficacious personalized medicine.

Citation Format: Shipra Gandhi, Arya Mariam Roy, Kazuaki Takabe, Spencer Rosario. Capecitabine, eribulin and paclitaxel differentially impact the metabolite pool in metastatic breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-06.