Abstract
Cancer is a complex, heterogeneous disease. Not only can a cancerous tumor have multiple cancer cell types within it, but it is also impacted by the surrounding tumor microenvironment. Made up of immune cells, blood vessels, fibroblasts, signaling molecules, and other cells around the tumor, the tumor microenvironment and the tumor itself hold a wealth of information for determining patient prognosis and clinical outcome.
The current standard in cancer classification and prognosis almost exclusively looks at the tumor in order to diagnose and classify a patient's cancer. That standard is TNM classification, or staging, which has been in use for over 80 years for a variety of cancers. But TNM staging is a means of understanding cancer, and the clinical outcome between two patients with the same diagnosis of advanced stage cancer can be vastly different using this method. It is not unheard of to have one advanced stage cancer patient remain stable for years after their diagnosis, while another patient succumbs early to the disease.
This difference in outcomes goes back to the fact that cancer is more than just the tumor cells, size, and invasion. Without the added information of the tumor microenvironment, incomplete information is being utilized for prognosis. Tumor microenvironment and patient immune status is being widely cited as the key to cancer prognosis and treatment for the future.
Current State of Cancer Prognosis
The current standard of TNM staging determines the severity of a person's cancer based on the size and/or reach of the primary tumor and if the cancer has spread in the body. TNM staging makes evaluations on the Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) for determining the stage and aggressiveness of the cancer. For the primary tumor, the size and/or extent of the tumor is being evaluated. For regional lymph nodes, the degree of lymph node involvement is evaluated. And for distant metastasis, the existence of metastasis is evaluated. The combined scores for TNM are then used to determine the cancer stage:
• Stage 0 – Carcinoma in situ
• Stage I, II, III – High numbers represent more extensive disease
• Stage IV – Cancer has spread to distant tissues and organs
Source: Galon et al., J Transl Med. 2012; 10: 205)
Classic TNM staging does evaluate key elements of a cancer biopsy sample, and the fact that it has been used for over 80 years as the gold standard in cancer prognosis is testament to its usefulness. However, TNM staging is limited in its ability to consider the broader tumor microenvironment, and the role the tumor microenvironment is playing in the patient's cancer. In particular, TNM staging does not account for the impact of the immune system and immune cells in and around the tumor. It is precisely this limitation of TNM that leads to the different clinical outcomes of patients with identical cancer stages. Modifying traditional cancer classification systems to reliably utilize both tumor and immune system features could dramatically improve prognosis accuracy and improve patient lives.
The Future State of Cancer Prognosis
Identifying how the immune system is interacting with a cancerous tumor is a very hot topic that is being investigated by academic researchers and companies developing new cancer therapies. The key for many of these projects is being able to accurately identify and quantitate the precise number of immune T cells in the tumor and in the invasive margin. Having the capability to do this is being shown to be a new way to determine cancer prognosis.
Through the utilization of advanced automated imaging solutions and Tissue Phenomics™ approaches from Definiens, the extensive experience of a pathologist in identifying cancer can be combined with the quantification of immune cells in both the tumor and invasive margin to result in a powerful cancer prognostic and classification system, the Immunoscore™. The Immunoscore works by staining two T cell populations (CD3+ and CD8+) in the core of the tumor and in the invasive margin of the tumor. The data results in a score that ranges from Immunoscore 0 (I0) when low densities of both cell types are found in both regions up to Immunoscore 4 (I4) when high densities of both cell types are found in both regions. Work published by Franck Pages, et al., has shown that after five years 4.8% of colorectal cancer patients with a high Immunoscore (I4) had relapsed and 86.2% were still alive whereas 72% of patients with a low Immunoscore (I0 or I1) experienced tumor recurrence and only 27.5% were still alive at 5 years.
The Immunoscore is in the process of being globally validated as a new tool for the classification of cancer, specifically colorectal cancer. The Immunoscore worldwide consortium, being led by the Society for Immunotherapy of Cancer (SITC), is composed of the European Academy of Tumor Immunology (EATI), the Cancer and Inflammation Program (CIP), the National Cancer Institute (NCI), the National Institutes of Health (NIH), and La Fondazione Melanoma. The ultimate goals of the Immunoscore consortium and the Immunoscore validation project is to better define the prognosis of colorectal cancer patients, better identify patients at high risk of tumor recurrence, help to predict and stratify patients that will benefit from cancer therapies, and ultimate help save the lives of patients with cancer.
Conclusion
The work being performed to validate the Immunoscore will be instrumental in the future evaluation and prognosis of cancer patients. The Immunoscore can change the landscape of how clinicians evaluate cancer biopsies and determine patient prognosis with an accuracy and confidence level the current TNM classification system cannot provide. This tool enables clinicians to provide the best in patient care and improvement in quality of life.