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Genetic predictors of tumor aggressiveness can often help make treatment decisions

BY RICHARD M. GOLDBERG, MD, physician-in-chief, Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Richard GoldbergWhen practicing oncologists make treatment decisions, they use their clinical skills to assess patients for their robustness, comorbidities and ability to tolerate treatment, and they size-up the tumor by staging and grading it. Such factors help determine whether a patient requires aggressive or moderate treatment, can be managed with a single treatment approach such as surgery or needs more than that.

Today, genetic factors that relate to tumor aggressiveness can often contribute to this critical decision. This possibility has emerged from research in genomics and tumor molecular biology, and it has moved into the clinic where it is allowing individualized treatment of patients and is making P4 medicine possible (see A Quiet Evolution).

Patients and tumors share many genes, of course, because tumors are derived from a patient’s own tissues. But tumor cells show radical genetic differences from healthy cells, including inactivated tumor-suppressor genes (analogous to defective brakes on a car) and hyper-activated tumor-promoting genes (analogous to a stuck accelerator pedal). Gene marker research—one area of focus here at the OSUCCC – James—is revealing molecular points of vulnerability in tumor cells, and medicinal chemists are developing rationally designed agents that target them.

Notable examples of these agents are inhibitors designed to block single driving mutations that are responsible for tumor growth in a subset of cancers. One such drug is imatinib, which inhibits the tyrosine kinase encoded by the BCR-ABL oncogene in chronic myelogenous leukemia and c-KIT tyrosine kinases overexpressed in gastrointestinal stromal tumors (see illustration). Taking this pill can convert these tumors from life threatening to chronic diseases. Research is also showing that patients’ genetics can predict how efficiently they will metabolize certain drugs and perhaps even help gauge their ability to tolerate treatment, a field known as pharmacogenetics.

When Lance Armstrong developed testicular cancer, the odds were good that he would withstand the rigors of treatment because he had tolerated the rigors of the Tour de France. An emerging science now seeks to identify genetic markers that will help determine which patients are the Lance Armstrongs and good candidates for aggressive therapy, and which patients are better managed with milder treatment options.

The burgeoning science of pharmacogenetics is revealing genetic differences that influence a patient’s ability to metabolize drugs, and we can test for these in a growing number of cases. For example, genetic testing is now routinely done to determine the dosing of the blood thinner warfarin.

Similarly, a genetic test is available for the drug irinotecan, which is used in the treatment of colorectal cancer, my clinical and research specialty. The drug is broken down by the enzyme uridine glucuronyl transferase (UGT). About 10 percent of the American population has a less efficient form of UGT, causing the activated form of irinotecan to remain longer in their system and cause problems such as diarrhea and low blood counts. Today, we can test patients for UGT, allowing us to individualize the dosage of the drug.

Sometimes genetic markers can indicate that further treatment is unnecessary. About 15 percent of colorectal cancers arise through a genetic alteration in one of four or five DNA mismatch repair genes. Patients with a defect in one of these genes have a better prognosis than the 85 percent of colon cancers that arise through chromosomal instability, the more common pathway.

For this reason, patients with early-stage colon cancers and microsatellite instability (a marker for a DNA mismatch repair defect) often don’t require chemotherapy after surgical removal of the tumor because outcomes are so good without it and are no better with drug therapy.

These advances all came about through research. These investigations require the proper collection and processing and storage of tumor tissue. At the OSUCCC – James Biorepository and Biospecimen Shared Resource, tumor and tissue specimens are frozen, rather than preserved in formaldehyde. This allows interrogation of the genetic structure of tumors for common genetic abnormalities and their use to develop treatments.

DNA was discovered in the 1950s, the human genome project was completed early in the 21st century, and the pace of progress related to unraveling the genome continues to accelerate. But the science is just in its infancy. Tools to look at the genome are available now, and we are still learning how to exploit them.

The knowledge we are gaining from this work is already revolutionizing the practice of medicine and will continue to do so for decades to come. But even today, genetic markers of tumor aggressiveness are being used in the clinic to identify individualized treatments that can be more effective and safer for our patients.

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The targeted drug imatinib (Gleevec®) inhibits the tyrosine kinase encoded by the BCR-ABL oncogene in chronic myelogenous leukemia (CML), and c-KIT tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. The drug is designed to bind to the active site of the BCR-ABL fusion protein. This prevents phosphorylation and activation of the substrate and blocks tumor-cell proliferation.

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