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Perou Shares How Deeper Sequencing of Genome Helps Define, Treat Breast Cancer Subtypes

Gina Columbus @ginacolumbusonc
Published: Thursday, Apr 28, 2016

Charles M. Perou, PhD

Charles M. Perou, PhD

For patients with early-stage invasive breast cancer and known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, ASCO’s February 2016 release of their evidence-based recommendations1 helped define appropriate use of biomarker assay results in guiding decisions on adjuvant treatment.

The recommendations state that beyond ER/PR and HER2 status, results from Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 have clinical utility in guiding treatment decisions on adjuvant therapy in subgroups of patients with breast cancer.

However, no biomarker test—except for ER/PR and HER2 status—was recommended for use to guide choices of specific drugs or treatment regimens.

The identification of intrinsic subtypes should be utilized to guide breast cancer treatment choices; however, more work needs to be done on sequencing the genome to determine what other biomarkers could carry significance in these patients, explains Charles M. Perou, PhD.

In an interview with OncLive, Perou, May Goldman Shaw Distinguished Professor of Molecular Oncology, professor of Genetics, and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, discusses how lobular breast cancer subtypes are used in clinical practice, what researchers have learned from sequencing the genome, and how determining intrinsic subtypes can help guide breast cancer therapy.

OncLive: How are lobular breast cancer subtypes being integrated into clinical arena?

Perou: There was a recent paper published from The Cancer Genome Atlas (TCGA) that was focused on studies in lobular breast cancers. From those studies, the main finding was a strong reinforcement that, on a molecular level, lobular breast cancer is really a distinct disease. It has a unique set of mutations, prominently including E-cadherin. However, another interesting finding included enrichment mutations in a gene called FOXA1.

Through gene expression profiling, we found 3 potential subtypes of lobular breast cancer, one of which showed a more proliferative phenotype and had a slightly worse prognosis than the other 2.

The other 2 are defined by other features in the microenvironment. In 1 case, it looked like there were immune-cell infiltrates. In another case, it looked like perhaps there were fibroblasts or other types of stromal-cell infiltrates—suggesting that there are important interactions between the tumor and the microenvironment. Perhaps we can target the immune infiltrate type with immunotherapy.

Can you go into detail with these expressive subtypes?

We gave them relatively simple names. We called one the “proliferative” type, as it showed higher expression of cell cycle–regulated genes and a worse prognosis. We called the second the “immune” type to signify the presence of immune cells—it actually had macrophages, which was somewhat different than what we see in ductal cancers. Finally, the “stromal” type has fibroblasts and other types of mesenchymal cells.

What are the immediate next steps for this project?

If possible, the next steps are to look at existing studies with the new lens and see if it has any therapeutic differences. We now have some tools to go in and look at earlier studies and link to some of these new findings.

The Breast International Group (BIG) 1-98 study, for example, was a very large aromatase inhibitor versus tamoxifen study. There were enough lobular breast cancers where they could look at the 2 arms between the lobular cancers and see a difference. That would be a great study to go back and look at these expression subtypes—to look at the FOXA1 mutations and see if the mutants behave differently than the wild-type cases.

FOXA1 is a cofactor with ER and it is required for, in some way, full ER activity. Mutations and a cofactor of ER certainly hint that there are going to be some differences in potential endocrine responses.

What are some unanswered questions with lobular breast cancers?

Is there a difference in responsiveness of aromatase inhibitors versus tamoxifen? A number of lobular cancers and their chemotherapy responsiveness is another place to look. These are maybe not as chemotherapy responsive in general as ER-positive cancers, which are also maybe not that chemotherapy responsive.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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