A collaboration announced last week between Ciphergen, the University College of London, and UCL BioMedica in which Ciphergen's proteomic tools will be used to screen 5,000 breast-cancer and control tissue samples for biomarker validation and discovery joins a swell of news involving molecular research with the potential to produce breast cancer diagnostics.
There does not seem to be any one thread connecting recent breast-cancer research and diagnostics news, aside from the fact that research into the disease receives a lot of funding, and that genomic and proteomic technologies may finally be producing leads in the area. Whether any of these efforts will reach the clinic in the form of a diagnostic, preferably cleared by the US Food and Drug Administration, is an open question. As is familiar in pharmacogenomics, some studies rely on small sample sizes, and success is never assured.
"There has been a lot of hype about some of the [potential molecular diagnostics] in the pipe that have really been too preliminary to receive the media attention they've gotten."
Should some of the current efforts achieve FDA clearance, developers of diagnostics can probably expect that clinicians will make use of them, said Debbie Saslow, director of breast and gynecologic cancer at the American Cancer Society. "I think one can use Herceptin [and HercepTest] as a model," she said. "That's a marker that pretty much every woman is tested for now, just as she is tested for estrogen-receptor positivity or progesterone," she said. "It doesn't even have to make that huge a difference, if you look at the survival rates for Herceptin," and as long as the test is easy to understand and relatively inexpensive, doctors will use it, she added.
"There has been a lot of hype about some of the [potential molecular diagnostics] in the pipe that have really been too preliminary to receive the media attention they've gotten," said Saslow. A lot of the new technologies "have high sensitivity, but they have this high false-positive rate, and that's just not acceptable," she said.
The expansion of Herceptin's market to include patients testing positive with HercepTest has triggered more Her2 testing and more interest in molecular diagnostics in breast cancer and cancer in general, David Flockhart, chief of the division of clinical pharmacology at the Indiana University School of Medicine, told Pharmacogenomics Reporter. "Everybody who is rational in oncology [thinks] that germ-line genetics, as well as tumor genetics, are going to help us predict efficacy, as well as side effects it has blasted through the hurdles," he said.
Impending Breast-Cancer PGx Diagnostics
Early last month, InterGenetics said it had completed its Oklahoma City headquarters, anticipating high demand for its OncoVue test, which genotypes a proprietary number of genes to identify women at risk for breast cancer. In June, the company signed a five-year deal with Toronto-based Tm Bioscience, which will supply InterGenetics with a minimum of $7.5 million worth of Tag-It reagents for the test.
In a company statement, Craig Shimasaki, InterGenetics CEO, estimated that OncoVue will play in a market as large as 30 million tests per year, growing at 2 million tests per year. The company hopes to get federal certification to begin testing this month, and it projected that its new lab will process as many as 15,000 tests in its first year.
A June Breast Cancer Research study using Norway-based DiaGenic's panel of 37 genes "accurately diagnosed breast cancer in [about] 82 percent of patients," the company said in a statement. A microarray-based test intended to detect breast cancer using gene expression analysis is scheduled for launch sometime in 2006, the company said.
Agendia, whose MammaPrint test assesses breast-cancer recurrence risk using expression data on 231 genes was granted ISO 17025 accreditation for its service with the test in September. According to the company, it is the first to be granted this accreditation for a microarray-based diagnostic test.
Designs on Diagnostics
Two small studies are the most recent news in breast-cancer personalized medicine, both of them with the aim of guiding therapy. The Karolinska Institutet in Sweden has been studying a 64-gene expression panel, while researchers at the Toronto Hospital for Sick Children and Princess Margaret Hospital have focused on two genes.
The Karolinska Institute's gene-expression profiles are intended to initially provide a prognosis for patients who have received adjuvant therapy for breast cancer. Last week, institute researchers published an article in Breast Cancer Research in which a 64-gene panel was used to discriminate between patients with a poor five-year prognosis from good-prognosis patients with a better prediction rate than histological grading. Within the good-prognosis group, the test differentiated those who did well with and without adjuvant therapy, the institute said.
"We are definitely expanding the study" from 159 patients to 2,000 to 3,000 patients for validation before attempting to create a diagnostic, said Per Hall, deputy head of the Karolinska Department of Medical Epidemiology and Biostatistics. "A diagnostic is only a first step," he said. If the researchers are successful in that, they aim to tailor the 64-gene expression panel to guide therapy to specific drugs, said Hall.
Bristol-Myers Squibb researchers have been involved in the early phase of research, but the collaboration "is not the most intense right now there are numerous other companies that have been discussing future collaborations with us," he added. If the group had $10 million, it could produce a diagnostic in about 18 months, but as of now, there is no definite timeline for any device, Hall said.
Guiding breast-cancer therapy with regard to a single pathway is the goal of researchers at the Toronto Hospital for Sick Children and Princess Margaret Hospital. The scientists reported in the Sept. 15 issue of Breast Cancer Research that two genes involved in the gamma-secretase pathway, Notch1 and Jagged1, prove to be good prognostic indicators for breast cancer survival.
In subsequent tests, the group is looking at using immunohistochemical tests, rather than in situ hybridization, said Michael Reedijk, a surgical oncologist in the breast cancer program at Princess Margaret. "We're in the process now of screening close to 1,000 women using similar techniques on tissue arrays, much like we did with the 184-[patient] tissue array" the group used in its previous research, said Reedijk.
Although the test is in an early stage, the two marker genes may prove to be useful as drug targets as well as prognostic biomarkers. "The beauty of all this is not only the identification of a potential marker for more aggressive breast cancer, but the inherent benefit that there are already drugs available that can target this pathway," Reedijk said. The group has not discussed with any drug makers the possibility of producing a test for use as a combination therapy with gamma-secretase inhibitor drugs, he said.
Companies with Diagnostics Plans
AutoGenomics and Targeted Molecular Diagnostics will develop microarray-based gene-expression assays for tumor response to therapies targeting Her1 and Her2 pathways, the companies said in July. Later assays will cover breast cancer response to therapies, apoptotic response, and resistance to chemotherapy, the companies said.
St. Louis-based Orion Genomics said in August that it will be collaborating with Washington University researchers to discover DNA methylation-based biomarkers of cancer and a tumor's response to certain drugs, with the goal of eventually producing a cancer test.
In June, Gennadi Glinsky of the Sydney Kimmel Cancer Center told Pharmacogenomics Reporter that Stratagene had licensed an 11-gene signature from the center for development of a possible diagnostic to predict tumor progression and metastasis, as well as identify so-called cancer stem cells.
"Our plan is to use the sets of genes that have predictive capabilities for prostate and breast cancer to develop diagnostic test kits based on our proprietary quantitative PCR FullVelocity technology," said Joe Sorge, Stratagene CEO, in a statement explaining the company's FullVelocity market strategy. "These kits should enable the detection of cancer at an earlier stage than is now possible and guide doctors as they make therapeutic decisions to treat cancers."
Last week, the Entertainment Industry Foundation's Women's Cancer Research Fund, the philanthropic arm of the entertainment industry, said it will provide $9 million over three years to seven biomedical-research institutions to discover early stage breast-cancer biomarkers. The effort is known as the EIF/WCRF Breast Cancer Biomarker Discovery Project, and is led by researchers at the Fred Hutchinson Cancer Research Center, the EIF said.
David Flockhart, the University of Indiana researcher, believes that the most promising area for breast cancer molecular diagnostic tests is the connection between germ-line genetics and drug response. That should hardly be surprising Flockhart is the principal investigator of the Pharmacogenetics Research Network's Consortium on Breast Cancer Pharmacogenomics, which will investigate variable responses to tamoxifen and hormone treatments in 500 breast cancer patients. Funded with $11.6 million, the project will study several objective measures of drug response, in addition to SNP genotyping.
Perlegen Sciences said in June that it will conduct a comparative whole-genome study of SNPs in patients with coronary heart disease, stroke, or breast cancer as part of the Women's Health Initiative, funded by the US National Heart, Lung and Blood Institute. Further financial details, along with details about whether the study might result in a diagnostic, were not disclosed.
Chris Womack ([email protected])