TGen-US Oncology data guides treatment of metastatic triple-negative breast cancer patients

December 6, 2012, The Translational Genomics Research Institute

Genomic sequencing has revealed therapeutic drug targets for difficult-to-treat, metastatic triple-negative breast cancer (TNBC), according to an unprecedented study by the Translational Genomic Research Institute (TGen) and US Oncology Research.

The study is published by the journal and is currently available online.

By sequencing, or spelling out, the billions of letters contained in the genomes of 14 tumors from ethnically diverse metastatic TNBC patients, TGen and US Oncology Research investigators found recurring significant mutations and other changes in more than a dozen genes. In addition, the investigators identified mutations previously unseen in metastatic TNBC and took the sequencing data into account in selection of therapeutic protocols specific to each patient's .

"This study stands as a one-of-a-kind effort that has already led to potentially beneficial clinical trials, and sets the stage for future investigations," said Dr. John Carpten, Ph.D., TGen's Deputy Director of Basic Science and Director of TGen's Integrated Genomics Division, and the study's senior author.

The most frequently mutated gene among the tumors (seven of 14) was the TP53 tumor suppressor, and aberrations were observed in additional including CTNNA1, which was detected in two of six (who typically have more aggressive and treatment-resistant disease). Alterations were also seen in the ERBB4 gene, known to be involved in mammary-gland maturation during pregnancy and lactation, but not previously linked to metastatic TNBC.

The study included an "outlier analysis," which assessed expression patterns for each tumor when compared against the other tumors examined in the study. Specific cancer genes overexpressed among tumors in the study's cohort included: ALK, AR, ARAF, BRAF, FGFR2, GLI1, GLI2, HRAS, HSP90AA1, KRAS, MET, NOTCH2, NOTCH3, and SHH. Significantly underexpressed cancer genes included: BRCA1, BRCA2, CDKN2A, CTNNA1, DKK1, FBXW7, NF1, PTEN, and SFN.

Each tumor was genomically unique, but nine of the 14 contained alterations in one or both of two particular cellular pathways: RAS/RAF/MEK/ERK and PI3K/AKT/MTOR. Targeted therapeutic intervention aimed at these pathways achieved impressive responses in several cases.

"Importantly, the analysis provided insights into the potential unique therapeutic vulnerabilities of each cancer," said Dr. Joyce O'Shaughnessy, M.D., the study's other co-lead author. Dr. O'Shaughnessy is a practicing oncologist with Texas Oncology—an affiliate of The US Oncology Network—and is the Celebrating Women Chair of Research at Baylor Charles A. Sammons Cancer Center.

Metastatic TNBC is a highly aggressive form of breast cancer that disproportionately affects African-Americans. It is called triple-negative because tumors do not express the estrogen receptor, progesterone receptor or HER-2, the biomarkers successfully targeted in most breast cancers.

Metastatic TNBC also has a poor prognosis once the cancer has spread to other organs, with a median survival rate among metastatic patients of only one year. While TNBC accounts for only about 15 percent of all breast cancers, its more aggressive biology makes it responsible for nearly one in four deaths related to this disease.

"The nature of this disease cries out for innovative research techniques such as whole genome sequencing coupled with new tools for data analysis," said Dr. David Craig, Ph.D., 's Deputy Director of Bioinformatics, and one of the study's co-lead authors.

"We are aware that these results are preliminary and based on a small series of patients," said Carpten. "However, our study will pave the way for new clinical trials and novel hypotheses for future testing in a very difficult to treat cancer."

Whole-genome sequencing of tumors and normal tissue was performed on Life Technologies Corporation's Applied Biosystems SOLiD™ 4.0 platform, and results were validated in a CLIA-certified laboratory.

Explore further: Study role testosterone may play in triple negative breast cancer

Related Stories

Study role testosterone may play in triple negative breast cancer

March 23, 2012
Could blocking a testosterone receptor lead to a new way to treat an aggressive form of breast cancer? That's a question researchers at Mayo Clinic in Arizona and the Translational Genomics Research Institute (TGen) are exploring. ...

First genome sequencing clinical trial for triple negative cancer points to new treatments

December 8, 2011
Initial results from an ongoing clinical trial, the first designed to examine the utility of whole-genome sequencing for triple negative breast cancer, were reported today during the CRTC-AACR San Antonio Breast Cancer Symposium.

Preliminary findings about whole-genome sequencing of triple-negative breast cancer presented

April 2, 2012
Because cases of Triple-Negative Breast Cancer (TNBC) are so genetically different, whole-genome sequencing is needed to detect the subtle molecular differences that might point to specific treatments for individual patients.

Different subtypes of triple-negative breast cancer respond to different therapies

June 27, 2011
Vanderbilt-Ingram Cancer Center researchers have identified six subtypes of an aggressive and difficult-to-treat form of breast cancer, called "triple-negative breast cancer (TNBC)."

Whole genome sequencing of rare olfactory neuroblastoma

May 23, 2012
The Translational Genomics Research Institute (TGen) and the Virginia G. Piper Cancer Center at Scottsdale Healthcare have conducted whole genome sequencing (WGS) of a rare nasal tract cancer called olfactory neuroblastoma ...

A form of small pox virus shows potential for treating triple-negative breast cancer

October 1, 2012
Researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City have shown that a new vaccinia virus, acting as both an oncolytic and anti-angiogenic agent, can enter and kill triple-negative breast cancer ...

Recommended for you

T-cells engineered to outsmart tumors induce clinical responses in relapsed Hodgkin lymphoma

January 16, 2018
WASHINGTON-(Jan. 16, 2018)-Tumors have come up with ingenious strategies that enable them to evade detection and destruction by the immune system. So, a research team that includes Children's National Health System clinician-researchers ...

Researchers identify new treatment target for melanoma

January 16, 2018
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a new therapeutic target for the treatment of melanoma. For decades, research has associated female sex and a history of previous ...

More evidence of link between severe gum disease and cancer risk

January 16, 2018
Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists ...

Researchers develop a remote-controlled cancer immunotherapy system

January 15, 2018
A team of researchers has developed an ultrasound-based system that can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.

Dietary fat, changes in fat metabolism may promote prostate cancer metastasis

January 15, 2018
Prostate tumors tend to be what scientists call "indolent" - so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, ...

Pancreatic tumors may require a one-two-three punch

January 15, 2018
One of the many difficult things about pancreatic cancer is that tumors are resistant to most treatments because of their unique density and cell composition. However, in a new Wilmot Cancer Institute study, scientists discovered ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.