Delineating intra-tumoral heterogeneity and tumor evolution in breast cancer using precision-based approaches

Abstract

The burden of breast cancer continues to increase worldwide as it remains the most diagnosed tumor in females and the second leading cause of cancer-related deaths. Breast cancer is a heterogeneous disease characterized by different subtypes which are driven by aberrations in key genes such as BRCA1 and BRCA2, and hormone receptors. However, even within each subtype, heterogeneity that is driven by underlying evolutionary mechanisms is suggested to underlie poor response to therapy, variance in disease progression, recurrence, and relapse. Intratumoral heterogeneity highlights that the evolvability of tumor cells depends on interactions with cells of the tumor microenvironment. The complexity of the tumor microenvironment is being unraveled by recent advances in screening technologies such as high throughput sequencing; however, there remain challenges that impede the practical use of these approaches, considering the underlying biology of the tumor microenvironment and the impact of selective pressures on the evolvability of tumor cells. In this review, we will highlight the advances made thus far in defining the molecular heterogeneity in breast cancer and the implications thereof in diagnosis, the design and application of targeted therapies for improved clinical outcomes. We describe the different precision-based approaches to diagnosis and treatment and their prospects. We further propose that effective cancer diagnosis and treatment are dependent on unpacking the tumor microenvironment and its role in driving intratumoral heterogeneity. Underwriting such heterogeneity are Darwinian concepts of natural selection that we suggest need to be taken into account to ensure evolutionarily informed therapeutic decisions.

The molecular evolution of cancer associated genes in mammals

“…It’s also important to take in account variation of evolution within tumour sub-populations 102 . As mutational pathways would also vary with the different challenges present in the tumour microenvironment and a cancer’s strategy can differ in response to this environment 103 . For example, in the tumours of the Devil Facial Tumour Disease, B2M is downregulated in order to evade detection by the immune system 104 .…”

Onco-Breastomics: An Eco-Evo-Devo Holistic Approach

“…The development of many tumors starts at the cell level through a process of somatic mutation that causes genetic variation/instability and arises through natural selection which acts as purifying selection that eliminates the deleterious mutations, or as positive selection, which maintains the functionally advantageous mutations, which allow, from a neoplastic perspective, aberrant proliferation, invasion, and metastasis [28][29][30]. Most tumoral clones share genomic rearrangements and cancer driver gene mutations, illustrating that such events may occur early in the cancer evolutionary process [31]. However, Ostrow et al (2014) showed that the cancer evolutionary process, dominated by positive selection of somatic mutations at a cell level, differs from organism's evolution, which is dominated by purifying selection affecting germline (hereditary) mutations at organismal level [29].…”

Exploring the Immunological Profile in Breast Cancer: Recent Advances in Diagnosis and Prognosis through Circulating Tumor Cells

“…Therapeutic approaches, such as immune checkpoint inhibitors (ICIs), adoptive cell therapies, and therapeutic vaccines, aim to bolster the immune response against cancer cells, including CTCs [145]. The success of immunotherapy against CTCs hinges on factors, such as CTC immunogenicity, antigen expression, and the immune system's capacity to recognize and eliminate these cells [146]. The TME, replete with immune-suppressive elements, further modulates the efficacy of immunotherapies against CTCs [147].…”