Genetic Profiling of Breast Neoplasms and Its Impact on Staging and Treatment.
Louis J. Auguste, MD, MPH, FACS
This presentation will show how:
- Different cellular proteins can help predict the outcome of Breast Cancer
- Genetic Profiling is a better prognosticator of outcome for Breast Cancer than the Traditional TNM Staging
- The new integrated Staging system of breast cancer is about to bring many changes in the treatment of breast cancer.
Breast Cancer has plagued mankind from the dawn of times. Attempts at treatment by hot cautery, by excision or by more radical procedures or simple observation are well documented. However, it was clear even then that not all cancers behave identically. Clinicians sought to identify features capable of predicting the outcome of the disease and guiding the physicians in their selection of therapeutic approaches. The first staging system was elaborated in Germany by Steinthal in 1904. It included: Stage I for small tumors limited to the breast, Stage II for tumors extending to the axillary nodes and Stage III for locally advanced tumors extending into the chest wall. In 1942, Pierre Denoix was the first to use the TNM system, based on the size of the tumors, the number and size of involved axillary lymph nodes and the presence or absence of distant metastasis. The first official clinical classification was released in Europe in 1958 by the UICC. The AJCC followed suit and after amending the UICC system, published its first staging system in 1977. These initial classifications were strictly based on the clinical features of the tumor at presentation and endeavored to match the stages with the patients’ survival. Since then, the AJCC/UICC has updated the staging system nearly every 5 years. The two main engines for these improvements were the creation of the National Cancer Database and the evolution of the statistical methods, that allowed to better define sub-categories within each stage. The universal adoption of these staging systems made it possible to conduct trials of single and/or combined modality therapies as well as adjuvant therapies that could be applied across the continents. It also allowed a better assessment of health care priorities, as well as the impact of different educational or screening interventions in given communities.
Starting in the 1980s, it became evident that some intrinsic cellular and molecular characteristics could play a major role in tumor behavior. The assessment of Sex Hormones status was the first break through. Their identification was greatly facilitated by the hybridization techniques, leading to immuno-histo-chemistry, FISH and CISH. At the same time, the Human Genome Project allowed to identify a whole array of genes, like HER2neu, whose expression or inhibition controls the tumor biology. The automatization of the process of sequential gene analysis led to a quicker analysis and reporting of the genetic profile of the tumors. These developments drew attention to the potentials for commercial exploitation of these advances. Among others, Genomics created Oncotype Dx® and Agendia, Mammaprint®, using respectively panels of 21 and 75 genes that have been found to predict outcomes in breast cancer more accurately than the traditional TNM system. The use of these gene panels has been integrated in the Eight edition of the AJCC Staging Manual which will establish the standards for the use of adjuvant hormonal, chemo and/or radiotherapy and the choice of agents, ushering in the era of so-called target therapy, where the therapeutic regimen will be specifically tailored to the individual patient or tumor. Unfortunately, it leaves out all the less developed countries where these diagnostic modalities are not yet available.