Written By Ryan Tong

VENTURES

written by RYAN TONG

Genomic Health For many of us, the ability to select from and customize products to suit our individual needs has long been a given.

From personalized ringtones to tailored wardrobes, we consume products everyday that match our personalities and needs. However, some of the most important products on the market, pharmaceuticals, have lagged behind in their adaptation for individualized use.

The Problem of Mass Drugs

In a controversial statement at the end of 2003, Allen Roses, worldwide vice-president of genetics at GlaxoSmithKline (GSK), said fewer than half of the patients prescribed some of the most expensive drugs actually derive any benefit from them. Many factors, ranging from drug concentration to rate of absorption to target of action, all play crucial roles in determining the functionality of a pharmaceutical agent. However, while the drug itself may be administered consistently, individual genetic differences can also affect the ultimate efficacy of drug treatments. In life-threatening diseases such as cancer, this is especially bad news. Drug response rates for cancer therapeutics are at times below 20%, and side effects from chemotherapies include extreme fatigue, nausea, diarrhea and hair loss. Often times, patients and their families are further burdened by the staggering cost of these pharmaceuticals. Two of today’s most popular cancer therapeutics, Herceptin and Avastin, cost about $3,100 and $4,400 per month, respectively. As a result of the low benefit, high risk and hefty prices of these drugs, there is growing demand for alternatives that will better select the correct, individualized treatment for patients.

The rise of molecular diagnostics

In recent years, the push for customized regimens and personalized care has spurred the growth of personalized medicine.

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The completion of the Human Genome Project in 2003 opened new doors for research, which is in turn increasing our understanding of genetic composition. The subsequent application of genomic knowledge to medical decision-making has blossomed into a new field known as pharmacogenomics, the tailoring of drugs to a person’s specific genetic makeup. At the forefront of this revolution is the billion dollar molecular diagnostics industry. Using biochemical assays, molecular diagnostics measure the gene expression profiles of patients and can correlate the findings with disease prevalence. Molecular diagnostics can look for biomarkers in a patient’s genome expression pattern to match a patient to the correct drug regimen. Such diagnostics are already being used by physicians to make informed treatment decisions for HIV, Human Papiloma Virus, Hepatitis C and cancer.

A Model Example

Genomic Health, a publicly traded biotechnology company located in Redwood City, California, was one of the first to pioneer the field of molecular diagnostics. One of the company’s primary products, Oncotype DX, is a genomic assay which assesses and predicts a patient’s likelihood of breast cancer recurrence and response to first line therapeutic treatments. Within two weeks of receiving tumor samples from the patient, Genomic Health can analyze the expression of 21 genes clinically correlated with the development of breast cancer. These results are used to calculate a score between zero and onehundred, which denotes that individual’s risk of relapse. The raw score can be used to identify low versus high risk patients; however, it can also be adjusted to account for different treatment regimens. “The true value of our assay lies in its power to predict how well a patient will do 5 to 10 years down the road”, says Maureen Cronin, VP of Translational Research at Genomic

Health. “The information is valuable to physicians, patients and payers in making the right treatment decisions.”

Developing the Gene Panel

The Oncotype DX is a multi-analyte assay, meaning that it measures the mRNA expression levels of 21 genes from multiple families correlated with the occurrence of breast cancer. But how did Genomic Health select this particular panel of genes from approximately 30,000 genes in the human genome? “By going through a combination of cancer literature, genomic databases, molecular biology studies and microarray data…we assembled an initial panel of 250 cancerrelated genes”, says Cronin. From those candidate genes, the company then conducted three independent exploratory studies with 447 patients to verify the correlations in the expression of each one of the genes with respect to relapse-free survival rates in cancer patients. From the correlation studies, 21 genes were selected for the final panel. Genomic Health then followed up by validating Oncotype’s ability to assess the benefit of Tamoxifen treatment in patients with low to medium scores (0-30). As a final test of their product’s predictive rigor, the company used preserved tumor samples of 790 patients with breast cancer and successfully predicted their individual outcomes after Tamoxifen and chemotherapy treatments.

The Major Players

The 21 genes measured in the assay can be categorized based on their functions in the cell. The first group is involved in cell proliferation, and includes genes such as Ki67, a nuclear protein regulating the cell cycle, and STK 15, which modulates chromosome structure during mitosis. Because most cancer cells differ from normal cells by their indefinite growth and proliferation, the examination of genes involved in cell cycle

Genes in the second group are indicative of a tumor cells’ propensity to metastasize and include genes like Stromelysin 3, which codes for a matrix metalloproteinase implicated in cell migration. The third family is comprised of genes involved in the expression of the Her2 cell surface receptor. Her2 receptors are believed to homodimerize and autophosphorylate each other when overexpressed. This activates a cascade of intracellular signaling pathways that result in uncontrolled cell proliferation and tumor development. The final set of genes is those which govern the activities of the estrogen and progesterone receptors. Because hormones such as estrogen and progesterone are important in stimulating cell and tumor growth, a measurement of the receptors’ response to hormone signals can suggest whether a patient would benefit from hormone therapy. Aside from these four main families of genes, the assay also measures a set of control genes, like GAPDH, a constitutively expressed housekeeping gene which can be used to normalize changes in specific gene expression levels between patients. Normalization is especially important because the contribution of each gene’s expression to the score calculation is weighted depending on its family’s overall correlation in causing breast cancer. For example, over-expression of genes in the Her2 and proliferation groups has been shown to cause breast cancer, and is thus more heavily weighted than over-expression of the hormone receptor family, which decreases the likelihood of recurrence. “This is a much more accurate prediction of patient outcome than traditional prognostic measures like tumor size, tumor grade or

immunohistochemistry markers that lack standardization and validation”, says Cronin. “It saves patients the pain of needlessly going through chemotherapy and the high cost of drugs.”

From Expression to Results

The expression levels of the 21 genes are measured using a process known as Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). In RT-PCR, mRNA from a tumor cell is incubated with DNA nucleotides, primers, reverse transcriptase, and DNA polymerase. Reverse transcriptase transcribes the mRNA into single-stranded DNA, which DNA polymerase then replicates into doublestranded cDNA fragments. After undergoing multiple cycles of heating and cooling to activate and deactivate the reaction, PCR exponentially amplifies the original RNA fragments into over one billion copies of DNA. Next sample is then run through an agarose gel to separate DNA fragments corresponding to the different genes. The relative expression level of each gene is measured by the fluorescence strength of its respective fragments upon UV exposure. Finally, these results are subjected to analysis by a standard algorithm to generate the recurrence score.

A Revolutionary Business Model

Because of its assay’s predictive power, Genomic Health has redefined the potential for the molecular diagnostics industry. “No one paid much attention to diagnostics in the past because they were general blood or urine tests that cost under $100”, says Vance Vanier, a partner at Mohr Davidow Ventures. “Genomic Health was one of the

first to truly break through the price barrier with a specialized genomic assay.” At $3,650 per test, the success of Oncotype DX has revolutionized the pricing of diagnostic products. “The reason we can sell our diagnostic test above traditional costs is because of the immense value that we bring to both patients and payors”, explains Kim Popovits, President and COO of Genomic Health. “Given that chemotherapy costs tens of thousands of dollars per patient per year, our test is a cost-effective predictive screen that allows doctors to tailor the treatment for the patients and scale down unnecessary costs for insurance providers.” In this sense, Genomic Health is at the forefront of personalized medicine. Investing more than $168 million in the research, development and clinical trials for its Oncotype product, the company is mirroring the business models of the pharmaceutical giants, who invest heavily in R&D in order to secure high margins (>70%) on their products. “We are witnessing a trend towards higher priced diagnostics and lower priced pharmaceuticals”, says Popovits. “As more and more people realize that big drugs on the market aren’t for everyone and realize the benefits of individually tailored drug treatments, the demand for diagnostic assays will continue to grow.” Genomic Health plans to expand its line of diagnostic tests for various types of solid tumors. The company plans to launch a diagnostic for prostate cancer next fall, and studies are under way for colon cancer. “The ultimate goal is to deliver maximum benefit to patients through individually designed treatments. The days of blockbuster pharmaceuticals are over and personalized medicine is here to say.”

RYAN TONG is a senior majoring in Biological Sciences. He is currently CFO of Stanford Scientific Magazine. Credit: sxc.com

regulation is important in deciding whether normal cells have the propensity to turn cancerous.

To Learn More

For more information on Genomic Health and its products, visit http://www.genomichealth.com.

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