Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes

Introduction The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that gen...

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Published in:Breast cancer research : BCR Vol. 21; no. 1; pp. 90 - 12
Main Authors: Sobral-Leite, Marcelo, Salomon, Izhar, Opdam, Mark, Kruger, Dinja T., Beelen, Karin J., van der Noort, Vincent, van Vlierberghe, Ronald L. P., Blok, Erik J., Giardiello, Daniele, Sanders, Joyce, Van de Vijver, Koen, Horlings, Hugo M., Kuppen, Peter J. K., Linn, Sabine C., Schmidt, Marjanka K., Kok, Marleen
Format: Journal Article
Language:English
Published: London BioMed Central 07.08.2019
BioMed Central Ltd
BMC
Subjects:
Adjuvant chemotherapy
Analysis
Biomarkers, Tumor
Biomedical and Life Sciences
Biomedicine
Breast cancer
Cancer Research
Care and treatment
Cellular signal transduction
Disease Susceptibility - immunology
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Gene Expression Profiling
Genetic aspects
Humans
Immunohistochemistry
Immunotherapy
Luminal breast cancer
Lymphocytes
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Lymphocytes, Tumor-Infiltrating - pathology
Mutation
Neoplasm Staging
Neoplasms - etiology
Neoplasms - metabolism
Neoplasms - mortality
Neoplasms - pathology
Oncology
Outcome and process assessment (Medical care)
Phosphatidylinositol 3-Kinase - genetics
Phosphatidylinositol 3-Kinase - metabolism
Phospholipids
PI3K pathway
PIK3CA mutations
Postmenopausal women
Prognosis
Proteins
Receptors, Estrogen - metabolism
Research Article
Surgical Oncology
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocyte Subsets - pathology
Tamoxifen
Transcriptome
Tumor-infiltrating lymphocytes
Tumors
PI3K pathway
mutations
Tumor-infiltrating lymphocytes
Luminal breast cancer
PIK3CA mutations
ISSN:1465-542X, 1465-5411, 1465-542X
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Summary:Introduction The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. Methods We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. Results CD8-positive lymphocytes were significantly more abundant in PIK3CA -mutated tumors (OR = 1.65; 95% CI 1.03–2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14–3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. Conclusion These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment.
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ISSN:1465-542X
1465-5411
1465-542X
DOI:10.1186/s13058-019-1176-2