A Phenomic Perspective on Factors Influencing Breast Cancer Treatment: Integrating Aging and Lifestyle in Blood and Tissue Biomarker Profiling

Abstract

Breast cancer is the most common malignancy among women worldwide. Over the last four decades, diagnostic and therapeutic procedures have improved substantially, giving patients with localized disease a better chance of cure, and those with more advanced cancer, longer periods of disease control and survival. However, understanding and managing heterogeneity in the clinical response exhibited by patients remains a challenge. For some treatments, biomarkers are available to inform therapeutic options, assess pathological response and predict clinical outcomes. Nevertheless, some measurements are not employed universally and lack sensitivity and specificity, which might be influenced by tissue-specific alterations associated with aging and lifestyle. The first part of this article summarizes available and emerging biomarkers for clinical use, such as measurements that can be made in tumor biopsies or blood samples, including so-called liquid biopsies. The second part of this article outlines underappreciated factors that could influence the interpretation of these clinical measurements and affect treatment outcomes. For example, it has been shown that both adiposity and physical activity can modify the characteristics of tumors and surrounding tissues. In addition, evidence shows that inflammaging and immunosenescence interact with treatment and clinical outcomes and could be considered prognostic and predictive factors independently. In summary, changes to blood and tissues that reflect aging and patient characteristics, including lifestyle, are not commonly considered clinically or in research, either for practical reasons or because the supporting evidence base is developing. Thus, an aim of this article is to encourage an integrative phenomic approach in oncology research and clinical management.

Keywords: biomarkers; breast cancer; clinical response; exercise; immunosenescence; lifestyle; physical activity; tumors.

Figure 1

Breast cancer prognosis, tumor properties, and clinical outcomes can be influenced by the characteristics of patients, including: age, body composition and adiposity, or exercise and physical activity. References are considered to be representative examples of robust human studies with breast cancer patients. (A) Cancer biomarkers can be assessed in tumor tissue or in blood and can provide information about prognosis and the clinical response to different treatments. (B) Some studies have shown that older age is associated with lower expression of tumor proliferative markers (e.g., Ki-67) and proteins implicated in tumor progression (e.g., P53), and higher expression of certain hormone receptors (e.g., ER, PR). (C) Higher adiposity has been associated with a lower expression of HER2, a lower magnitude of tumor immune cell infiltration and lower activation status of tumor-resident CD8+ T cells. (D) Bouts of exercise and physical activity have been shown to decrease some inflammatory markers (e.g., IL-2) and increase pro-angiogenic factors (e.g., PLGF and EPCs expressing VEGFR-2). Higher tumor vascularity could facilitate the delivery of drugs to a tumor. (E) The effectiveness of breast cancer treatments can be influenced by tumor properties [shown in panel A] and the characteristics of patients [shown in (B–D)]. (F) In turn, interaction between tumor properties, the characteristics of patients, and the effectiveness of breast cancer treatments can influence clinical outcomes. EPCs: Epithelial Progenitor cells, ER: Estrogen Receptor, HER2: Human Epidermal Growth Factor Receptor-2, IL-2: Interleukin 2, IL-6: Interleukin 6, KI-67: nuclear protein Ki-67, PGLF: Placenta Growth Factor, PR: Progesterone Receptor, P53: tumor protein 53, TILs: tumor Infiltrating Lymphocytes, VEGFR-2: Vascular Endothelial Growth Factor Receptor-2. Figure created with BioRender.com. Adapted from “tumor Microenvironment 2” and “Types of Cancer Treatment”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates.