R. Ramanathan1, A. Raza1, J. Young2, J. Sturgill1, D. Lyon1, K. Takabe2 1Virginia Commonwealth University,Richmond, VA, USA 2Roswell Park Cancer Institute,Breast Surgery,Buffalo, NY, USA
Introduction: Sphingosine-1 phosphate (S1P) is bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. The dynamics of the circulating S1P levels during the postoperative period, however, have yet to be delineated. In this study, we analyze plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to control healthy volunteers.
Methods: With institutional review board approval, plasma S1P was measured in 20 healthy women without breast cancer (control) as well as 158 patients with breast cancer who underwent adjuvant chemotherapy with or without irradiation after surgical resection. Among patients with breast cancer, postoperative plasma S1P was measured two weeks prior to adjuvant therapy (baseline), prior to the 4th cycle of chemotherapy (midpoint) and two weeks after completion of adjuvant therapy (completion). Correlations with demographics, treatments and inflammatory markers were analyzed with the use of chi-square tests, paired and non-paired t-tests and ANOVA analyses.
Results: 452 plasma S1P samples among 158 breast cancer patients were analyzed, along with 20 control healthy volunteers. Mean S1P levels did not differ between cancer patients and controls (1221.7 vs. 1139 pmol/mL, p=NS). S1P levels similarly did not associate with age or race in our cohort. Smoking was associated with higher S1P levels (1445.4 vs. 1163.3 pmol/mL, p<0.05). Midpoint S1P levels during adjuvant therapy were lower than baseline (1088.8 vs. 1221.8, p<0.05), with near return to baseline after completion (1121.5 vs. 1221.8, p=0.06), indicating a relationship between chemotherapy and circulating S1P. Furthermore, while stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2 enriched and triple negative breast cancer as compared to luminal type cancer (1119.2 and 1167.1 vs. 1280.8, p<0.05). Additionally, patients with intermediate and high grade tumors similarly had lower S1P than those with low grade tumors (1230.0 and 1176.5 vs. 1570.8 pmol/mL, p<0.05), further suggesting an inverse relationship between plasma S1P levels and tumor aggressiveness. There were no significant differences based on chemotherapy regimen and radiation.
Conclusions: We found that plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that plasma S1P levels do not reflect S1P secretion from cancer cells.