TGen-US Oncology data guides treatment of metastatic triple-negative breast cancer patients
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 Molecular Cancer Therapeutics 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 genetic profile.
"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 Cancer 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 tumor suppressor genes including CTNNA1, which was detected in two of six African American patients (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 Breast Cancer 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., TGen'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.
Provided by The Translational Genomics Research Institute
- Study role testosterone may play in triple negative breast cancer Mar 23, 2012 | not rated yet | 0
- First genome sequencing clinical trial for triple negative cancer points to new treatments Dec 08, 2011 | not rated yet | 0
- Preliminary findings about whole-genome sequencing of triple-negative breast cancer presented Apr 02, 2012 | not rated yet | 0
- Different subtypes of triple-negative breast cancer respond to different therapies Jun 27, 2011 | not rated yet | 0
- Whole genome sequencing of rare olfactory neuroblastoma May 23, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be villous adenoma in colon, if there are no villi there
1 hour ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
- More from Physics Forums - Medical Sciences
More news stories
Cancer survivors are no more likely to stop smoking, cut down on alcohol, or exercise more often than the general population, according to new research published in the British Journal of Cancer today (Wednesday)
Cancer 50 minutes ago | not rated yet | 0
Beta-blockers, normally used for high blood pressure, could enhance the effectiveness of chemotherapies in treating neuroblastoma, a type of children's cancer, according to a new study published in the British Jo ...
Cancer 1 hour ago | not rated yet | 0
A Japanese cancer specialist said Wednesday she has started the world's first clinical trial of a powerful, non-surgical, short-term radiation therapy for breast cancer.
Cancer 1 hour ago | not rated yet | 0
The gap between life expectancy in patients with a mental illness and the general population has widened since 1985 and efforts to reduce this gap should focus on improving physical health, suggest researchers in a paper ...
Cancer 14 hours ago | not rated yet | 0
By studying the roles two proteins, thrombospondin-1 and prosaposin, play in discouraging cancer metastasis, a trans-Atlantic research team has identified a five-amino acid fragment of prosaposin that significantly reduces ...
Cancer 15 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Scientists supported by the National Institutes of Health have a new theory as to why a woman's fertility declines after her mid-30s. They also suggest an approach that might help slow ...
30 minutes ago | not rated yet | 0 |
Medical researchers discover new ways to target, develop and design drugs to prevent and treat viral infection
Researchers at the University of Alberta have discovered a new drug target, developed a new drug and identified a new way to design drugs—all of which could be a winning combination in the battle against viruses.
50 minutes ago | not rated yet | 0 |
(Medical Xpress)—A report published today shows a 2.6% decrease in the amount of alcohol sold per adult in Scotland in the year following the introduction of the Alcohol etc. (Scotland) Act in October 2011.
7 seconds ago | not rated yet | 0
(Medical Xpress)—Do ethicists engage in better moral behavior than other professors? The answer is no. Nor are they more likely than nonethicists to act according to values they espouse, according to researchers from the ...
49 minutes ago | not rated yet | 0
The University of Gothenburg Vaccine Research Institute (GUVAX) announces successful results in a placebo controlled phase I study of an oral, inactivated Escherichia coli diarrhea vaccine.
20 minutes ago | not rated yet | 0
(Medical Xpress)—Preschoolers universally recognize that one's choices are not always free – that our decisions may be constrained by social obligations to be nice to others or follow rules set by parents ...
30 minutes ago | not rated yet | 0