Intratumoral Morphological Heterogeneity of Breast Cancer As an Indicator of the Metastatic Potential and Tumor Chemosensitivity

Abstract

Breast cancer (BC) demonstrates considerable intratumoral morphological heterogeneity. The aim of this work was to evaluate the relationship among different morphological structures, the rate of metastasis, and efficacy of neoadjuvant chemotherapy (NAC) in NAC-treated (n = 427) and NAC-naïve (n = 249) BC patients. We also studied the involvement of an epithelial-mesenchymal transition (EMT) in the development of the intratumoral morphological heterogeneity of BC. We found a significant association between the intratumoral morphological heterogeneity and the rate of BC metastasis and response to NAC, which, in most cases, correlated with the presence of alveolar and trabecular structures. In particular, the rate of lymph node metastasis in tumors containing alveolar and trabecular structures was higher compared to that in tumors lacking such structures. NAC-treated patients with alveolar and trabecular structures had a high distant metastasis rate and a low metastasis-free survival rate. Furthermore, alveolar and trabecular structures were found to be associated with a lack of response to NAC. Interestingly, the association between alveolar structures and a high distant metastasis rate was found only in NAC-unresponsive patients, whereas the association between trabecular structures and an increased distant metastasis was revealed in responders. Alveolar structures were associated with chemoresistance only in patients with lymph node metastases, whereas trabecular structures were associated with chemoresistance only in patients without lymph node metastases. In general, increased intratumoral morphological diversity correlated with considerable chemoresistance and a high metastasis rate of BC. We found variable expressions of epithelial (EPCAM and CDH1) and mesenchymal (ITGA5, ITGB5, CDH2, CDH11, TGFb2, ZEB1, MMP2, DCN, MST1R) markers and, thus, different EMT manifestations in different morphological structures. Therefore, intratumoral morphological heterogeneity of BC may serve as an indicator of the metastatic potential and tumor chemosensitivity.

Different Morphological Structures of Breast Tumors Demonstrate Individual Drug Resistance Gene Expression Profiles

“…A poor response to NAC is associated with the presence of alveolar, trabecular, or discrete groups in breast tumors, while the association was more significant in premenopausal patients. In contrast, a good response to chemotherapy was found in BCs with solid structures [2].…”

“…Such intratumor morphological heterogeneity is a common phenomenon in IC NST. Up to 80% of IC NST shows the presence of 3-5 different types of morphological structures [2].…”

Impact of intratumor heterogeneity on diffusion-weighted MRI as a prognostic indicator in lower rectal cancer

“…Furthermore, the mixture of cancer nests with these different histologies has frequently been reported, and the pattern of stromal distribution in histologically mixed tumors is generally heterogeneous. Previous studies reported that the heterogeneity of stromal distribution in pathological ndings has potential as a prognostic marker [10,11], suggesting that the outcomes of patients may be estimated in the pre-operative setting by evaluating the cancer stromal pattern indirectly using imaging modalities.…”

“…Previous studies identi ed stromal heterogeneity as a prognostic or therapeutic biomarker, and showed that a heteronomous stromal pattern in pancreatic and breast cancers correlated with a poor outcome [10,11]. The tumor stroma ratio is used as a prognostic marker in gastric and colon cancers [12,13].…”

MicroRNA‐708‐3p mediates metastasis and chemoresistance through inhibition of epithelial‐to‐mesenchymal transition in breast cancer

“…show that these EMT stimulators are also closely correlated with metastasis and chemoresistance in breast cancer. 32,33 Interestingly, recent studies show that overexpression of EMT stimulators is caused by the downregulation of tumor suppressor miRNAs. 34,35 In the present study, for the first time, we found that miR-708-3p negatively regulates EMT in breast cancer cells.…”