Letter to the Editor: Cancer stem cell and oncomatrix biomarkers predict chemotherapy response and survival in triple-negative breast cancer

Abstract

We read with great interest the clinical study published in the World Journal of Clinical Oncology by Depar et al investigated the associations of cancer stem cells (CSC) markers (CD44, CD24, ALDH1) with chemotherapy response and survival in triple-negative breast cancer (TNBC) patients. Current advanced approaches for the treatment of chemoresistant TNBC focus on mRNA-based therapy as a form of personalized medicine designed to overcome conventional therapeutic resistance. Among the clinical findings, the study by Depar et al also focuses on the availability of personalized medicine alternatives for patients with hard-to-cure cancers, using Pakistan as an example of a developing economy. Beyond the other findings of the study, one particular idea is worth noting: Advanced diagnostics are needed not to replace current approaches, but to be applied in low-income economies that cannot afford high-cost diagnostic methods. Indeed, the development of expensive therapies for resistant cancers has been limited in effectiveness by population-specific genetic patterns. Screening studies aimed at identifying substitute biomarkers associated with the CSC microenvironment or tumor extracellular matrix properties could provide a basis for selecting personalized therapies. This "leapfrogging" approach appears to be especially beneficial for high-risk patients with chemoresistant TNBC.

Key Words: Breast cancer; Cancer; Cancer stem cells; Cell regulation; Epithelial-mesenchymal transition; Extracellular matrix; Leapfrogging; Personalized medicine; Triple-negative breast cancer; Tumor

Core Tip: Advanced diagnostics are required not as replacements for existing approaches, but for application in developing economies that lack the resources to support high-cost diagnostic techniques. The use of advanced substitutional biomarkers associated with cancer stem cells or tumor extracellular matrix properties could enable leapfrogging toward personalized therapy.

TO THE EDITOR

Progress of the therapies for cancer patients faced with the economic and educational barriers in low-income and developing countries. The clinical study by Depar et al[1] published in the World Journal of Clinical Oncology not only investigated the associations of cancer stem cells (CSC) markers (CD44, CD24, ALDH1) with chemotherapy response and survival in triple-negative breast cancer (TNBC) patients, but focuses on the availability of personalized medicine alternatives for patients with hard-to-cure cancers, using Pakistan as an example of a developing economy[1]. The authors faced the challenge of a lack of advanced methods for cancer diagnosis and therapy and should propose alternative approaches for the application of unconventional methods.

Current advanced approaches for the treatment of chemoresistant TNBC focus on mRNA-based therapy as a form of personalized medicine designed to overcome conventional therapeutic resistance. Most of the targets for mRNA therapy in TNBC involve tumor-specific neoantigens, such as those resulting from mutations in TP53, ADD2, SLC25A18, SSH1, related to aberrant signaling pathways associated with cancer cell proliferation and immune evasion[2]. The clinical applications of the mRNA technology required not only the scientific basics and good manufactory practice pharmacy facility, for example the hospital exemptions conditions. This results in extreme complexity in the production process and very high costs, which prevent these drugs from being used across a wide range of populations[3]. Recent investigations have also begun to explore the role of immunological patterns in predicting advanced therapies effectiveness, including the modulation of tumor-infiltrating lymphocytes, the reprogramming of the tumor microenvironment, and the identification of immune checkpoint signaling as critical regulatory mechanisms[4-6]. These studies aimed to enhance the immune system’s ability to recognize and eliminate resistant cancer cells, thereby improving the therapeutic efficacy and durability of clinical responses in patients with TNBC.

Therefore, the current progress in advanced TNBC treatments requires justification of low-cost surrogate biomarker panels available for community hospitals. The study by Depar et al[1] identified a CSCs phenotype as a strong and independent prognostic and predictive marker, but usual assays for CD44/CD24/ALDH1 require advanced immunohistochemistry or flow cytometry that are not always feasible in resource-limited settings. The aim of this letter was to discuss the unique immuno-biomarkers related to the TNBC microenvironment, primarily related to the patterns of the microenvironment properties of CSCs.

The nature of CSC-related alternative biomarkers

The study by Depar et al[1] presented the regionally adapted clinical trial designs leveraging CSC phenotype. The study found the CSC+ subgroup has far lower pathologic complete response (pCR) with standard neoadjuvant chemotherapy. The authors found that specific CSC phenotype was associated with markedly reduced pCR to neoadjuvant chemotherapy and inferior overall survival, independent of traditional clinicopathologic factors[1]. These results underscore the prognostic relevance of CSC markers in an understudied population, where TNBC burden is high and outcomes are often compromised by socioeconomic barriers[7,8].

The CSC biomarker approach could be supported by the specific properties of the niche extracellular matrix (ECM) (i.e. oncomatrix)[9], which not only ‘exist’ as a biomarker, but support the cellular viability and assist the chemoresistance of the tumor[10]. It remains questionable how these biomarkers could be applied into the therapy, because of the complexity and non-invasibility of the oncomatrix disruptions. However, emerging research suggests that targeting the dynamic interactions between CSCs and their surrounding ECM could open novel therapeutic windows. For example, enzymatic remodeling of matrix components, selective inhibition of matrix crosslinking enzymes, or targeting ECM-derived signaling molecules might attenuate CSC support systems without compromising normal tissue integrity[10].

Implement adaptive “microtrials” in South Asia where CSC+ patients are randomized to receive low-cost or repurposed drugs (e.g., metformin, salinomycin, or statins, which have preclinical CSC-targeting effects) as adjunctive therapy. The trials could use a “fast-fail” adaptive design, rapidly retiring ineffective combinations and reprioritizing those that show early signals in real-world Pakistani cohorts. This integrates biology-based precision medicine in a cost-sensitive framework.

The potential advantages of diagnostic methods related to ECM

The intersection of public health and molecular epidemiology focuses on personalized medicine approaches that consider population genetic features. However, only ten percent of cases had the CSC phenotype, yet it carried a fourfold hazard for death suggesting a disproportionate public health burden within a minority subset. The link CSC phenotyping to geo-epidemiologic data such as environmental exposures, reproductive factors, and socioeconomic indices to explore whether this aggressive phenotype clusters geographically or demographically. If so, community-level interventions addressing potential upstream biological triggers (e.g., vitamin D deficiency, endocrine disruptors, or chronic inflammation) could reduce incidence of CSC-driven TNBC, not just improve treatment response.

The advanced therapies for solid tumors face not only immunological and mechanical barriers but also a lack of proven diagnostic tools, which hinders curability in patients with solid tumors[11,12]. In contrast, the use of leapfrogging techniques based on the identification of oncomatrix features and other surrogate microenvironmental biomarkers to predict tumor response could be highly beneficial[13,14].

CONCLUSION

The development of high-cost therapies for resistant cancers faced with the population genetic patterns limited their effectiveness. The screening studies aimed to identify the substitutional biomarkers associated with the CSC or tumor ECM properties, could lead to causality to choice of personalized therapy.