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. 2020 Feb 14;12(2):446.
doi: 10.3390/cancers12020446.

Accelerated Partial Breast Irradiation: Macrophage Polarisation Shift Classification Identifies High-Risk Tumours in Early Hormone Receptor-Positive Breast Cancer

Sören Schnellhardt  1 , Ramona Erber  2 , Maike Büttner-Herold  3 , Marie-Charlotte Rosahl  1 , Oliver J Ott  1 , Vratislav Strnad  1 , Matthias W Beckmann  4 , Lillian King  5 , Arndt Hartmann  2 , Rainer Fietkau  1 , Luitpold Distel  1
Affiliations

Accelerated Partial Breast Irradiation: Macrophage Polarisation Shift Classification Identifies High-Risk Tumours in Early Hormone Receptor-Positive Breast Cancer

Sören Schnellhardt et al. Cancers (Basel). .

Abstract

Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163- cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low; M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.

Keywords: CD163; CD68; accelerated partial breast irradiation; early breast cancer; hormone receptor-positive; prognosis; tumour associated macrophages.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) In-breast recurrence-free survival and disease-free survival of the studied patient cohort analysed with the Kaplan–Meier method and log-rank test. (B) Scanned image of a representative breast cancer tissue microarray core (200× magnification). (C) Epithelial tumour compartment marked with an image analysis software. (D) Representative examples of M1 (IHC CD68+; blue) and M2 (IHC CD68+/CD163+; violet) tumour associated macrophages (TAMs). (E,F) Stromal and intraepithelial cell density distributions of M1 and M2 TAMs in samples from four different locations. The central line represents median values while the box is indicative of the interquartile range (IQR). Whiskers represent 1.5× IQR or minimum/maximum. Outliers are indicated by points (up to 3× IQR) or asterisks (>3 IQR). Black bars signify p < 0.05 in Student’s t-test.
Figure 2
Figure 2
Disease-free survival analysed with the Kaplan–Meier method and log-rank test according to macrophage densities in invasive front samples: (A,B) M1 macrophage densities in the stromal and intraepithelial compartment. (C,D) M2 macrophage densities in the stromal and intraepithelial compartment. (E,F) Disease-free survival according to TAM polarisation shift classifications applied to the stromal and intraepithelial compartment of invasive front samples. The table located in the lower right section explains how results from (A–D) were combined to create the TAM shift classification.
Figure 3
Figure 3
(A,C) Disease-free survival analysed with the Kaplan–Meier method and log-rank test according to TAM polarisation shift classifications based on stromal and intraepithelial macrophage densities in central tumour samples. (B,D) Versions of (A) and (C) that compare disease-free survival of the M2-shifted group to the remaining two groups. The tables below the survival plots give a detailed explanation of group compositions. (E) Intraepithelial macrophage density distributions in invasive front samples according to the TAM polarisation shift classification. The scale on the left indicates M1 macrophage densities (blue) while M2 cell densities can be found on the right (red). The central line represents median values while the box is indicative of the interquartile range (IQR). Whiskers represent 1.5× IQR or minimum/maximum. Outliers are indicated by points (up to 3× IQR) or asterisks (>3 IQR). Black bars signify p < 0.05 in Student’s t-test.
Figure 4
Figure 4
Disease-free survival analysed with the Kaplan–Meier method and log-rank test according to (A) Ki67 and (B,C) the TAM shift classification applied to invasive front samples. In-breast recurrence-free survival analysed with the Kaplan–Meier method and log-rank test according to (D) Ki67 and (E,F) the TAM shift classification applied to invasive front samples. In (B,C,E,F), M2-shifted was compared to the remaining two groups of the TAM shift classification. The table below the survival plots gives a detailed explanation of group compositions.
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