57 Altered Biomechanics Drives Outcome in Breast Cancer: A New Avenue for Oncology Biomarkers

Background

Biomechanics has recently emerged as a hallmark of tumor development and response to treatment. However, complex biological architectures that underline aggressive functional biomechanical phenotypes in solid tumors are poorly understood. Part of the complexity of resolving molecular mechanisms underlying these altered mechanical states is due to the nonlinearity between molecular biology and mechanical functional phenotypes. In other words, different tumor microenvironment, as characterized by genomics or proteomics, could result in similarly altered functional mechanical phenotypes that drive invasion and treatment resistance.

Materials and Methods

We developed a dual approach to resolve molecular drivers of altered mechanics in breast cancer that drive outcome and treatment response. In this work, we used 2 complimentary approaches on 2 separate clinical cohorts to resolve both the spatial proteomics profile and the mechanical functional phenotype of breast cancer and to identify biomechanical biomarkers that drive long-term outcomes in breast cancer. The first cohort used to investigate spatial proteomics profiles included 700 primary breast cancer samples (from 113 women with 20-plus years of follow-up), where a custom-developed imaging mass cytometry panel of 65 biomarkers was used to resolve cancer signaling, immune, and stromal cells, structures, and microenvironmental cues. The patient cohort included 20-plus years of follow-up, with up to 6 samples per patient from 64 patients alive 12 years post diagnosis, and 49 patients lost to breast cancer deaths. Patients were treated with surgery, radiation, chemotherapy, endocrine therapy, or combinations thereof. In this cohort, we identified recurring spatial patterns of markers within the tumor microenvironment and defined the spatial heterogeneity of such patterns. We derived a new, 3-parameter quantitative metric of preferential spatial colocalization between different cells or structures and used this metric to stratify patients with the aid of single and multivariate survival analysis. These data identified tumor-immune-stromal spatial patterns associated with breast cancer outcomes and their spatial scale. The second cohort included patients from a study conducted at the Breast Clinic in Basel, Switzerland, where fresh samples, collected within routine clinical workflow, were characterized with the ARTIDIS device to identify the altered nanomechanical phenotypes in breast cancer.

Results

Among the results, we identified a strong biological signature of aggressive mechanical phenotypes in the presence of spatial regions of hypoxia-driven epithelial-to-mesenchymal transition that mechanistically drives poor outcome.

Conclusion

This study confirms the importance of biomechanical drivers in breast cancer and offers a mechanistic interpretation of altered biomechanical phenotypes that drive poor outcomes in breast cancer.