Effects of estrogen-deprivation on ER+ breast cancer

Hormone Therapy for ER+/HER2- Breast Cancer

In the clinical management of ER/PR+ (estrogen receptor/progesterone receptor-positive), HER2- (human epidermal growth factor receptor 2-negative) breast cancer patients, anti-estrogen therapy, commonly referred to as hormone therapy, is frequently administered post-surgery. According to the latest NCCN guidelines (2024, version 3), for patients with localized breast cancer (pT1–3, N0/N+), endocrine therapy (e.g., Tamoxifen for up to 10 years) is recommended for both premenopausal and postmenopausal women. For those with a high risk of recurrence, as indicated by a high Recurrence Score (RS ≥ 26) from genetic testing, chemotherapy may also be added.

Although current evidence for immunotherapy in non-triple negative breast cancer (TNBC) is limited, especially for ER+ subtypes, high-risk patients might benefit from the addition of CDK4/6 inhibitors like abemaciclib. Ongoing research could potentially elevate the status of immunotherapy to a first-line treatment in combination with hormone therapy for ER+ breast cancer in the future.

Tumor Infiltrating Lymphocytes (TILs) and Their Clinical Significance

Pathology reports for breast cancer typically include the proportion of tumor infiltrating lymphocytes (TILs). The clinical significance of TILs varies among breast cancer subtypes. In TNBC, a higher TIL count is associated with a better response to treatment. Conversely, in HR+/HER2- breast cancer, the average TIL count is lower due to the subtype’s lower immunogenicity. This phenomenon may be related to factors such as higher Th2 infiltration, lower MHC class II expression, and reduced interferon-γ (IFN-γ) signaling, which collectively result in fewer CD8+ cells.

Current literature presents mixed conclusions regarding the prognostic value of TILs in ER+/HER2- breast cancer, with some studies linking higher TIL counts to poorer outcomes. As such, routine use of TIL counts as a prognostic marker for this subtype is not yet supported.

Impact of Aromatase Inhibitors on Immune Environment

Studies have shown that the number of infiltrating immune cells increases significantly in ER+/HER2- breast cancer patients after treatment with aromatase inhibitors (AIs). To investigate whether estrogen deprivation alters the immune status of cancer cells, Jody et al. observed an upregulation of immune-related genes, including CCL5, CCL22, and CCL14, in patients treated with neoadjuvant AIs over two weeks.

In vitro experiments with estrogen-deprived ER+ MCF-7 cells revealed a significant increase in CCL5, CCL22, and CXCL16 gene expression from 24 to 120 hours post-seeding. This upregulation was not observed in ER- SKBR3 cells. Further protein-level analysis using multiplex chemokine/cytokine assays showed significant increases at 72 and 120 hours but not at 24 hours, suggesting that genetic changes precede protein expression.

Co-Culture Experiments and Immune Cell Recruitment

To determine whether estrogen-deprived cancer cells can recruit immune cells, Jody et al. conducted co-culture experiments with MCF-7 cells and human PBMCs in a transwell setup. The results showed a significant increase in PBMC migration towards estrogen-deprived MCF-7 cells after four hours, a process inhibited by chemokine-blocking peptides. Flow cytometry analysis indicated a notable increase in CD4+ cells and a trend towards decreased CD11c+ and CD14+ cells among the migrated PBMCs.

In Vivo Evidence from Mouse Models

In an orthotopic estrogen-deprivation mouse model treated with Letrozole (an AI) for 25 days, tumor growth was significantly inhibited. Immunohistochemistry revealed increased CD3+ T cell infiltration post-treatment. Flow cytometry confirmed an increase in CD4+ T cells and a decrease in CD19+ B cells, indicating an enhanced immune response.

Goat says

It’s time to challenge the notion that only immune cells can secrete certain chemokines. Cancer cells within the tumor microenvironment can also act as immune regulatory cells, capable of secreting chemokines and cytokines under specific stimuli.

In ER+/HER2- breast cancer, due to ER regulation, different subclones may exhibit various phenotypes based on the estrogen concentration gradient. This makes the tumor heterogeneity in ER+/HER2- breast cancer higher than in TNBC. However, after treatment with AIs or anti-estrogen therapies, these cells may still show different levels of immunogenicity. Therefore, when combining these treatments with immunotherapy, the impact of tumor heterogeneity must be considered.

References

• NCCN Guidelines, 2024, Version 3
• “Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment”
• “Oestrogen deprivation induces chemokine production and immune cell recruitment in in vitro and in vivo models of oestrogen receptor-positive breast cancer”