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. 2018 Jun 22;20(1):62.
doi: 10.1186/s13058-018-1003-1.

Immune characterization of breast cancer metastases: prognostic implications

Maria Vittoria Dieci  1   2 , Vassilena Tsvetkova  3 , Enrico Orvieto  4 , Federico Piacentini  5 , Guido Ficarra  6 , Gaia Griguolo  3   7 , Federica Miglietta  3   7 , Tommaso Giarratano  7 , Claudia Omarini  8 , Serena Bonaguro  3 , Rocco Cappellesso  9 , Camillo Aliberti  10 , Grazia Vernaci  3   7 , Carlo Alberto Giorgi  7 , Giovanni Faggioni  7 , Giulia Tasca  3   7 , Pierfranco Conte  3   7 , Valentina Guarneri  3   7
Affiliations

Immune characterization of breast cancer metastases: prognostic implications

Maria Vittoria Dieci et al. Breast Cancer Res. .

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available.

Methods: Secondary lesions from 94 BC patients, 43 triple-negative (TN) and 51 HER2-positive, were evaluated for TILs and expression of CD8, FOXP3, and PD-L1 by immunohistochemistry.

Results: TILs levels on metastasis were generally low (median 5%) and did not differ between TN and HER2+ tumors. Younger patients showed significantly lower TILs (p = 0.002). In HER2+ patients, TILs were higher in lung metastases as compared to other sites (p = 0.038). TILs composition was different across metastatic sites: skin metastases presented higher FOXP3 (p = 0.002) and lower CD8/FOXP3 ratio (p = 0.032). Patients treated for metastatic BC prior to biopsy had lower CD8 (overall: p = 0.005, HER2+: p = 0.011, TN: p = 0.075). In TN patients, median overall survival (OS) was 11.8 and 62.9 months for patients with low and high TILs, respectively (HR 0.29, 95%CI 0.11-0.76, log-rank p = 0.008). CD8/FOXP3 ratio was also prognostic in TN patients (median OS 8.0, 13.2, and 54.0 months in 1st, 2nd and 3th tertile, log-rank p = 0.019). Both TILs and CD8/FOXP3 ratio were independent factors at multivariate analysis. Counterintuitively, in HER2+ BC, low TILs tumors showed better prognosis (median OS 53.7 vs 39.9 months in TILs low and TILs high, not statistically significant).

Conclusions: Our findings indicate the relevance of TILs as prognostic biomarker for TNBC even in the advanced setting and provide novel hypothesis-generating data on potential sources of immune heterogeneity of metastatic BC.

Keywords: HER2; Metastatic breast cancer; PD-L1; Triple negative; Tumor-infiltrating lymphocytes.

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Conflict of interest statement

Ethics approval and consent to participate

This research has been conducted in accordance with the Declaration of Helsinki. The study protocol has been approved by the Ethics Committee of Istituto Oncologico Veneto IRCCS of Padova and the Ethics Committee of Modena University Hospital. Patients signed the informed consent form.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Correlations between immune parameters. Heatmap showing Spearman’s coefficients and statistical significance (p values) for the correlation between immune markers in the overall population (a), TN cohort (b) and HER2+ cohort (c). Significant p values in bold. PD-L1 programmed death-ligand 1, TILs tumor-infiltrating lymphocytes
Fig. 2
Fig. 2
CD8, FOXP3, and CD8/FOXP3 ratio in skin versus other metastasis sites. Boxplots comparing CD8, FOXP3, and CD8/FOXP3 ratio in skin versus other metastasis sites in all patients and in TN and HER2+ cohorts separately (a). Pictures showing a skin metastasis with high TILs and low CD8/FOXP3 ratio and a liver metastasis with low TILs and high CD8/FOXP3 ratio (b). HER2 human epidermal growth factor receptor-2, TILs tumor-infiltrating lymphocytes, TN triple negative.
Fig. 3
Fig. 3
Overall survival (OS) according to immune biomarkers assessed on metastasis. OS in the triple-negative cohort according to TILs (a), CD8/FOXP3 ratio (b) and CD8/FOXP3 ratio combined with TILs (c); OS in the HER2+ cohort according to TILs levels (d). CI confidence interval, HR hazard ratio, OS overall survival, TILs tumor-infiltrating lymphocytes
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