Breast cancer complexity: implications of intratumoral heterogeneity in clinical management

Abstract

Generation of intratumoral phenotypic and genetic heterogeneity has been attributed to clonal evolution and cancer stem cells that together give rise to a tumor with complex ecosystems. Each ecosystem contains various tumor cell subpopulations and stromal entities, which depending upon their composition can influence survival, therapy responses and global growth of the tumor. Despite recent advances in breast cancer management, the disease has not been completely eradicated as tumors recur despite initial response to treatment. In this review, using data from clinically relevant breast cancer models, we show that the fates of tumor stem cells/progenitors in the individual tumor ecosystems comprising a tumor are predetermined to follow a limited (unipotent) and/or unlimited (multipotent) path of differentiation which create conditions for active generation and maintenance of heterogeneity. The resultant dynamic systems respond differently to treatments, thus disrupting the delicate stability maintained in the heterogeneous tumor. This raises the question whether it is better then, to preserve stability by preventing take-over by otherwise dormant ecosystems in the tumor following therapy. The ultimate strategy for personalized therapy would require serial assessments of the patient’s tumor for biomarker validation during the entire course of treatment that is combined with their three dimensional mapping to the tumor architecture and landscape.

pH-sensitive polymeric nanoparticles of mPEG-PLGA-PGlu with hybrid core for simultaneous encapsulation of curcumin and doxorubicin to kill the heterogeneous tumour cells in breast cancer

“…Recently, cancer stem cells (CSCs) have been considered to be a source for initiation, invasion, metastasis and recurrence of breast tumour [39,40]. It has become a new strategy to simultaneously target the CSCs and the differentiated tumour cells by concomitant delivery of CSCs-targeting agents and traditional chemotherapeutics.…”

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results

“…In breast cancer, tumor hypoxia has been recognized as an important driver of intratumoral heterogeneity which in turn leads to the development of cell clones with an aggressive and treatment-resistant phenotype characterized by rapid progression, treatment failures, and patient deaths [1,2,[6][7][8][9]. Prior studies that investigated tumor hypoxia in breast cancer using the PET/CT imaging with the radiotracer [ 18 F]fluoromisonidazole ([ 18 F]FMISO) have shown that higher [ 18 F]FMISO-tumor-to-background-ratio (TBR) and estrogen receptor negativity were independent predictors of shorter disease-free survival, where higher [ 18 F]FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers [55].…”

“…Breast cancer (BC) is a complex disease with remarkable intratumoral heterogeneity which leads to varied genetic, phenotypic, and behavioral characteristics; clinical presentations; and treatment responses [1][2][3][4][5][6]. Tumor hypoxia has been recognized as an important feature and a key driver of BC heterogeneity [7] that leads to the development of cell clones and an aggressive and treatment-resistant phenotype characterized by rapid progression and poor prognosis [8].…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…This is the antithesis of molecular‐targeted therapy, the targets of which are the components of complex intracellular interactomes (Figure ). As in any complex system, phenotypic effects of molecular targeting in this case are unpredictable. Immune checkpoint therapy is a striking example of the success of the afore‐mentioned concept, but its complexity is manifested here by its rather high toxicity, and the enormous variability of patients’ responses—ranging from none to complete remission which presents an important problem …”