Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer

Abstract

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman's coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p < .001), lower median (0.42 (0.02), p < .001), a negative skewness with lower magnitude (- 1.65 (0.77), p = .001), higher entropy (4.35 (0.64), p = .007) and lower kurtosis (5.13 (3.99), p = .001). Peri-tumoural PUFA had a lower mean (p < .001), lower median (p < .001), a positive skewness with higher magnitude (p = .005) and lower entropy (p = .002). Peri-tumoural SFA had a higher mean (p < .001), higher median (p < .001), a positive skewness with lower magnitude (p < .001) and lower entropy (p = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude (p = .01) and lower kurtosis (p = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness (r_s = - .64), PUFA entropy (r_s = .63) and SFA skewness (r_s = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

Keywords: Breast cancer; Heterogeneity; Inflammation; Lipid composition; Oestrogen receptor.

Figure 1

Flowchart of two-group cross sectional research study design. Thirteen postmenopausal patients with oestrogen receptor-positive, invasive ductal carcinoma and 13 age-matched healthy controls were eligible at initial screening and were consented into the study. All participants and controls underwent fasting blood tests on serum full lipid profile (total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol to HDL ratio) and C-reactive protein (CRP) prior to chemical shift-encoded imaging on a clinical 3T MRI scanner. Fat mapping image analysis was conducted to compute spatial heterogeneity of lipid constituents in the peri-tumoural region (Peri-P) and the whole breast of participants and controls (WB-P, WB-C). Mann Whitney U or Wilcoxon signed rank paired statistical tests were subsequently performed to compare values between the locations. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Figure 2

Peri-tumoural and whole breast lipid composition maps, obtained from MRI scans, in a typical participant (65-year-old woman with oestrogen receptor-positive breast cancer) and a control participant (overlaid on anatomical image). (a–c) MUFA, PUFA and SFA maps in the whole breast of a control participant (WB-C). (d–f) MUFA, PUFA and SFA maps in the peri-tumoural region of a participant (Peri-P). (g–i) MUFA, PUFA and SFA maps in the whole breast of a participant (WB-P). For the control participant, the mid-sagittal slice is shown. For the participant, the slice at the greatest dimension of the tumour (central grey area) is shown. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Figure 3

The group difference in (a) mean, (b) median, (c) skewness, (d) entropy and (e) kurtosis of MUFA, PUFA, SFA in the whole breast of control participants (WB-C) (n = 13), the peri-tumoural region (Peri-P) (n = 12) and the whole breast of participants (WB-P) (n = 12). Each dot represents a peri-tumoural or whole breast mean fraction or spatial heterogeneity, and the dots are organised in three columns corresponding to locations. All spatial heterogeneities are shown in boxplots to indicate the minimum, 25th percentile, median, 75th percentile and maximum. Mann Whitney U (participants versus control participants) and Wilcoxon signed rank paired (within participants) tests were performed between the groups. Statistical significant p values are marked by *(< .017 after Bonferroni correction for multiple comparisons), **(< .01), ***(< .001). ‘ns’: not significant. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Figure 4

Scatter plots showing correlations of (a) MUFA skewness (n = 12), (b) PUFA entropy (n = 12) and (c) SFA skewness (n = 12) with CD163 antibody on tumour-associated macrophages. The Spearman’s rank correlation coefficients (r_s) and 95% confidence intervals (CI) are shown for each plot. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.