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Cancer Genome Research Studies: An Evolving Story


 Jennifer Ivanovich

From the February 2013 issue of YWBCP magazine
By Jennifer Ivanovich, MS
Genetic Counselor
Washington University School of Medicine

We’ve all heard the news stories — promising scientific discoveries that will one day lead to improvements in human health. For some, the enthusiasm quickly wanes as little, if any, impact is ever realized. By contrast, the enthusiasm for large-scale cancer genomic studies remains steady, as the rapidly advancing technology provides an intricate picture of cancer never seen before. One such study was presented in October 2012 by the Cancer Genome Atlas Network.

Before we discuss that study’s findings, let’s review some information. Young survivors are knowledgeable of the tests currently used to characterize breast cancers, such as the histopathology, or description of the cells where the tumor arose, ER, PR and HER2neu status, as well as stage information. However, these pathologic, receptor and stage data provide a minimal characterization of a woman’s breast cancer. While all stage IIB, ER+PR+Her2Neu- ductal breast cancers may sound the same, their underlying genetic compositions are intrinsically different. Every woman’s breast cancer is unique.

It was not until the relatively recent advancement of genomics, the study of the entire genetic makeup, that the genetic diversity of breast cancers could be delineated. Why does this delineation matter? Detailed analyses of large collections of tumors allows for more precise diagnostic information. If the basic makeup of a tumor is understood, then tailored treatments that attack that tumor’s essential features can be used.

In 2000, an important advance in characterizing breast tumors began with the use of DNA microarray technology, which incorporates data from hundreds of genes within a given tumor. Four intrinsic subtypes were delineated based on specific gene clusters, combinations of multiple genes expressed in the tumors. These subtypes are Luminal A, Luminal B, Her2-enriched and Basal-like subtype (1). The research provided a new mechanism for classifying breast tumors based on the tumor’s molecular composition rather than the features identified under the microscope.

Data from tumor DNA microarray analyses helped to shape breast cancer care. Clinical tests designed to predict which tumors would benefit from chemotherapy were soon developed. One example is the Oncotype DX® test, which analyzes 21 genes in early stage ER+ breast tumors. The tumor analysis provides information about breast cancer recurrence risk and helps to assess which women with early stage breast cancer may benefit from chemotherapy. This positive clinical intervention was realized because of the research.

Advances in genome, protein and other molecular technologies were proceeding at an unprecedented pace. It was becoming possible to integrate RNA and protein expression data with extensive genetic analyses of a tumor. A more explicit picture of the composition of different cancer types was starting to emerge. A new chapter was being written.

Given the scientific and clinical significance of the advancing technology, the National Institutes of Health (NIH) developed and funded the Cancer Genome Atlas Project (TCGA) in 2009. The goal of the project is to categorize the genetic changes in more than 20 cancer types, including lobular and ductal breast cancer (see

That leads us to the report published in October 2012 by the Cancer Genome Atlas Network (2). It was one of the most comprehensive analyses of breast cancer reported to date because it incorporates data across six different analytical platforms. Integration of multiple different analyses provided the most detailed blueprint of the distinct molecular operations with each breast cancer subtype. 825 primary breast tumors were included, with all six analyses reported for over 500 tumors. Ten percent of the study population was women diagnosed < 40 years.

Some highlights of the study included:

  • Genes previously implicated in breast cancer were identified. A number of new significantly mutated genes were also identified. This finding expands the catalog of genes necessary for breast cancer development and progression.
  • Across the four subtypes, only three genes – TP53, PIK3CA and GATA3 – were abnormal or mutated in more than 10 percent of all tumors.
  • There were unique genetic and molecular compositions within each subtype.

    - The mutation rate was highest in the Basal-like subtype but expressed the smallest number of significantly mutated genes. This finding suggests it may take abnormalities in only a few key genes to drive cancer growth.

    - The Luminal A and Luminal B subtypes (which include estrogen- and progesterone-positive tumors) demonstrated a lower mutation rate but showed a larger number and greater diversity of significantly mutated genes. These data suggest multiple genetic pathways can lead to the development of these two subtypes.

    - Only half of clinical Her2+ tumors fall into the Her2-enriched subtype, with the remaining tumors observed in the Luminal A and B subtypes. These data suggest there are least two types of clinical Her2+ tumors, each with different molecular compositions.
  • The Basal-like subtype showed a genomic makeup similar to ovarian serous tumors. The Basal-like subtype is often referred to as triple negative breast cancer because many, but not all, Basal-like tumors are negative for estrogen, progesterone and Her2 receptors. The finding of the molecular similarity between the Basal-like subtype and ovarian cancer allows for treatment comparisons between the two cancers.

Led by Charles Perou and Matthew Ellis, this study is a critical chapter in an evolving classification of breast cancer based on its molecular architecture. Now, scientists can begin to develop targeted therapies that exploit the specific molecular blueprint of each woman’s tumor.

Advocates and researchers alike will justly argue it is not enough. Improvements in clinical care must be realized from the Cancer Genome Atlas Project to maintain our enthusiasm for cancer genome science. We can only wait to see how the story progresses. Let’s hope for a story that has a good ending, with lower mortality rates and fewer treatment-related side effects.