Combining Genomic Profiling and Tissue-Based Biomarker Assays to Aid in the Early Detection and Prevention of Cancer

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Genomic sequencing of precancerous lesions to improve prevention and early detection of cancer was a major focus at the recent American Association of Cancer Research (AACR) annual meeting. The results of the Pre-Cancer Genome Atlas (PCGA) project could enable early therapeutic intervention to prevent precancerous lesions from progressing into cancer. During the plenary session, Dr Bert Vogelstein of Johns Hopkins Medicine discussed the need for early detection to identify the genetic mutations that advance precancer to cancer. The message of early detection was further emphasized by several presenters, including Dr Scott Lippman of the University of California, San Diego, who discussed within the PCGA initiative, and AACR 2017-2018 President Dr Elizabeth Jaffee of Johns Hopkins Medicine during the summary session. Understanding changes in genetic alterations and mutational burden over time can be used to understand the tipping point that advances precancer to cancer and can also be used to monitor a patient’s response to therapy. As Dr Alice Shaw of the Massachusetts General Hospital Cancer Center demonstrated in her presentation, therapies targeting epidermal growth factor receptor (EGFR) mutations can be altered if new mutations are found or if the tumors become resistant to therapy.

Although research in the PCGA is focused on the genetic alterations that lead to carcinogenesis, researchers also discussed how mutations alone do not support tumor growth; rather, the tumor must be in a supportive microenvironment. If tumor microenvironment characteristics, including the immune response and supporting stromal cells, are essential in enabling tumor progression, and if genetic mutations may not be sufficient in predicting tumorigenesis, how can tissue-based biomarker assays be used in parallel with genomic profiling assays to best predict the onset of tumorigenesis and potentially predict a therapeutic strategy?

Tissue-based biomarker assays such as immunohistochemistry (IHC) could be used to put the gene expression profiles and mutational analyses into the context of the tissue. In the tumor microenvironment, physical interactions between cells types are critical for understanding their function. The changes in spatial distribution of blood vessels invading tumor nests, or CD8 T cells moving from the surrounding stroma into tumor nests to directly interact with and kill tumor cells can only be measured in the tissue context. However, there are features of the tumor microenvironment that may be best captured by profiling gene signatures. Cytokines released from tumor-associated macrophages that promote tumorigenesis or angiogenesis may more readily be captured by gene expression profiling. When paired with IHC to examine the distribution of macrophages and interaction with blood vessels, the pro-tumorigenic effects of macrophages may be interpreted regionally.

Flagship is using their Computational Tissue Analysis (cTA™) platform to precisely quantify many features of an IHC biomarker assay that can be challenging to visually quantify, including stain intensity, distance measurements, density of distribution among the tumor nests and surrounding stroma and low abundance cell types, to define these characteristics of the tumor microenvironment. 

With new immunotherapy targets continuing to emerge, and with the ongoing development of combination therapies, including targeted therapies, chemotherapy, radiation therapy, and checkpoint inhibitors, understanding the stromal components and immune infiltrates in tissue may be key to enabling a precise and targeted therapeutic strategy for cancer prevention and early intervention.

Allison Harney
Scientist III
Flagship Biosciences