Subtyping Breast Cancer: Genome Analysis Opens Door to New Era in Targeted Therapies

Emma Hitt, PhD
Published Online: Tuesday, December 4, 2012
Charles M. Perou, PhD

Charles M. Perou, PhD

The clinical subtyping of breast cancer appears to be coming into a golden era as an increased understanding of subtyping promises to help advance treatments and outcomes for patients. A comprehensive review published this year by Matthew J. C. Ellis, MB BChir, PhD, and colleagues with The Cancer Genome Atlas (TCGA) Research Network has provided new information about these subtypes in addition to identifying a new classification of HER2-positive disease, and has also suggested a rationale for new treatment options in each subtype. The study builds on one of the seminal works in breast cancer subtyping, published in 2000 by Charles M. Perou, PhD, and colleagues, which at the time provided a much more detailed understanding of gene signatures in malignant breast tissue than had previously existed, although the initial characterization was limited due to the technique of choice (DNA microarray) and sample size.

Current Treatment Paradigms

Currently, clinicians recognize the following forms of disease: luminal A and luminal B, two cancer subtypes that express the estrogen and progesterone receptors (ER and PR, respectively); human epidermal growth factor receptor 2 (HER2)-positive tumors, which express the HER2 protein; and basal-like tumors, which lack HER2, ER, and PR (often referred to as triple-negative breast cancers [TNBCs], but approximately 25% of TNBCs fall into other micro-RNA subtypes).

Surgery and radiation represent frontline options for patients with breast cancer. Typically, a chemotherapeutic regimen including a taxane is then given to systemically suppress the regrowth of the tumor and prevent metastasis. During initial diagnosis, hormone receptor and HER2 expression are also determined. When the ER and PR status is positive, anti-hormone drugs such as tamoxifen are often indicated. Trastuzumab (Herceptin), a monoclonal antibody against HER2, can be used in HER2-positive disease. In addition, targeted therapeutics have improved the prognosis of patients with these specific cancer subtypes.

Despite the advances in targeted therapy, significant limitations persist. Anti-hormone compounds in hormone receptor-positive disease are able only to suppress the growth of cancer cells. They do not kill these cells, and this gives the tumor time to circumvent hormone signaling and resume unchecked growth, often leading to relapse and resistance. Anti-HER2 therapy is successful in treating a large number of patients, but the development of resistance is a common feature of HER2-positive disease. In addition, roughly half of HER2-positive patients with previously untreated metastatic disease do not respond to trastuzumab when used in combination with chemotherapy . The reason for this lack of response is unclear. No approved targeted therapies yet exist for the basal-like breast cancers, since they do not express any known targetable proteins. This leaves only the nonspecific chemotherapy option for patients with this disease.

An Expanded Analysis of Breast Cancer Subtypes

The TCGA network, through its pivotal new work, ultimately may help to expand the treatment options for breast cancer by increasing the understanding of the subtypes. The network, launched in 2006 through a collaboration of the National Cancer Institute and the National Human Genome Research Institute, brings together researchers from approximately 15 institutions, including centers at Washington University in St. Louis, Missouri, where Ellis is based.

In the breast cancer study, the researchers combined a variety of techniques using tumor samples from 825 patients in an effort to definitively characterize the breast cancer subtypes. They also hoped to elucidate specific pathways of disease to improve the current standards of care. Six features of genes across the entire exome were analyzed, including DNA copy number, mutation, DNA methylation, mRNA expression, micro-RNA expression, and protein expression.

Overall, the team concluded that diverse genetic and epigenetic alterations in breast cancers could be classified into the four major biological subtypes, and that “much of the clinically observable plasticity and heterogeneity occurs within, and not across,” those subtypes.

Snapshot of Mutated Genes in Breast Cancer Subtypes

Snapshot of Mutated Genes in Breast Cancer Subtypes

The TCGA study included an analysis of the significantly mutated genes in 498 tumor samples correlated with genomic subtype. Adapted from Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours [published online ahead of print September 23, 2012]. Nature. 2012;490(7418):61-70. doi: 10.1038/nature11412.

New Findings in HER2-Positive Breast Cancer

The study elucidated distinct subtypes of HER2-positive cancer. Nearly half of the samples revealed the classically-defined HER2-positive disease where mRNA and protein levels were elevated. In the other half, the gene expression signature indicated strong similarity to the luminal subtype.

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