Immune characterization of breast cancer metastases: prognostic implications

Abstract

BackgroundTumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available.MethodsSecondary 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.ResultsTILs 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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1003-1) contains supplementary material, which is available to authorized users.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…In contrast to NSCLC, where regulatory approval for anti‐PD1/PD‐L1 therapy (pembrolizumab) is based on PD‐L1 positivity assessed on tumor cells , in BC, PD‐L1 seems to be predominantly expressed by stromal compartment . However, so far, no consistent data exist on the possible biological and clinical implications of a differential expression of PD‐L1 by either tumor cells or tumor‐infiltrating immune cells.…”

“…The immune landscape of metastatic lesions may be even more complex when considering that a trend in the opposite direction with regard to TILs has been reported. In particular, results from two large retrospective cohorts of patients with MBC showed that TILs tended to decrease from primary to metastatic lesions in the TN subtype , especially in patients receiving CT (for the advanced disease) prior to metastasis biopsy .…”

“…It remains therefore unclear whether PD‐L1 expression assessed on secondary rather than primary lesions may provide additional and clinically relevant information. Indeed, Dieci et al reported that whereas TILs assessed on metastatic lesions from patients with TNMBC were positively associated with outcome, stromal PD‐L1 expression did not retain any prognostic value (with either 5% or 1% cutoff for positivity) .…”

Should Tumor Infiltrating Lymphocyes, Androgen Receptor, and FOXA1 expression predict Clinical Outcome in Triple Negative Breast Cancer Patients?

“…Four-micrometer-thick sections were cut from FFPE blocks and mounted onto slides. The slides were processed and stained as previously reported [26].…”

“…BRCA1 is a suppressor gene, whose dysfunction is linked to a higher risk of developing cancer, such as inhibition of DNA repair enzymes Poly [ADP-Ribose] Polymerase 1 (PARP1) [24]. Moreover, our team has shown in TNBC tumors that the association between nuclear PARP1 and cytoplasmic NHERF1 (Na+/H+ Exchanger Regulatory Factor 1) expression, a scaffolding protein with oncogenic activity [25], identified a subgroup of patients with a shorter survival [26].…”