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

Marcelo Sobral-Leite, Izhar Salomon, Mark Opdam, Dinja T. Kruger, Karin J. Beelen, Vincent van der Noort, Ronald L. P. van Vlierberghe, Erik J. Blok, Daniele Giardiello, Joyce Sanders, Koen van de Vijver, Hugo M. Horlings, Peter J. K. Kuppen, Sabine C. Linn, Marjanka K. Schmidt, Marleen Kok

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number90
Pages (from-to)90
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
Publication statusPublished - 2019

Cite this

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. / Cancer-immune interactions in ER-positive breast cancers : PI3K pathway alterations and tumor-infiltrating lymphocytes. In: Breast Cancer Research. 2019 ; Vol. 21, No. 1. pp. 90.
@article{28363847a3b741f7af203caf025813c8,
title = "Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes",
abstract = "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.",
author = "Marcelo Sobral-Leite and Izhar Salomon and Mark Opdam and Kruger, {Dinja T.} and Beelen, {Karin J.} and {van der Noort}, Vincent and {van Vlierberghe}, {Ronald L. P.} and Blok, {Erik J.} and Daniele Giardiello and Joyce Sanders and {van de Vijver}, Koen and Horlings, {Hugo M.} and Kuppen, {Peter J. K.} and Linn, {Sabine C.} and Schmidt, {Marjanka K.} and Marleen Kok",
year = "2019",
doi = "10.1186/s13058-019-1176-2",
language = "English",
volume = "21",
pages = "90",
journal = "Breast Cancer Research",
issn = "1465-542X",
publisher = "BioMed Central",
number = "1",

}

Sobral-Leite, M, Salomon, I, Opdam, M, Kruger, DT, Beelen, KJ, van der Noort, V, van Vlierberghe, RLP, Blok, EJ, Giardiello, D, Sanders, J, van de Vijver, K, Horlings, HM, Kuppen, PJK, Linn, SC, Schmidt, MK & Kok, M 2019, 'Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes' Breast Cancer Research, vol. 21, no. 1, 90, pp. 90. https://doi.org/10.1186/s13058-019-1176-2, https://doi.org/10.1186/s13058-019-1176-2

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

In: Breast Cancer Research, Vol. 21, No. 1, 90, 2019, p. 90.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cancer-immune interactions in ER-positive breast cancers

T2 - PI3K pathway alterations and tumor-infiltrating lymphocytes

AU - Sobral-Leite, Marcelo

AU - Salomon, Izhar

AU - Opdam, Mark

AU - Kruger, Dinja T.

AU - Beelen, Karin J.

AU - van der Noort, Vincent

AU - van Vlierberghe, Ronald L. P.

AU - Blok, Erik J.

AU - Giardiello, Daniele

AU - Sanders, Joyce

AU - van de Vijver, Koen

AU - Horlings, Hugo M.

AU - Kuppen, Peter J. K.

AU - Linn, Sabine C.

AU - Schmidt, Marjanka K.

AU - Kok, Marleen

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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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UR - https://www.ncbi.nlm.nih.gov/pubmed/31391067

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DO - 10.1186/s13058-019-1176-2

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