A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer.

Abstract

BACKGROUND:

Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients.

METHODS:

Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF).

RESULTS:

We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients.

CONCLUSIONS:

This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.

• Authors: Claire Bonneau, Antoine Eliès, Yann Kieffer, Brigitte Bourachot, Sylvain Ladoire, Floriane Pelon, Delphine Hequet, Jean-Marc Guinebretière, Christophe Blanchet, Anne Vincent-Salomon, Roman Rouzier, Fatima Mechta-Grigoriou
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 22 Issue 1 Pg. 76 (07 14 2020) ISSN: 1465-542X [Electronic] England
• PMID: 32665033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Receptors, Estrogen
• Receptors, Progesterone
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (immunology, metabolism, pathology, therapy)
• Cancer-Associated Fibroblasts (immunology, pathology)
• Carcinoma, Ductal, Breast (immunology, metabolism, pathology, therapy)
• Carcinoma, Lobular (immunology, metabolism, pathology, therapy)
• Case-Control Studies
• Combined Modality Therapy
• Female
• Follow-Up Studies
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology, pathology)
• Middle Aged
• Neoplasm Recurrence, Local (immunology, metabolism, pathology, therapy)
• Prognosis
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Survival Rate
• Tumor Microenvironment (immunology)