A genetic match: These CAT scans show the best response to a targeted cancer drug in a lung-cancer patient deemed likely to respond based on a genetic screen. Before treatment (top), the left side of the lung, normally black, is nearly filled with a whitish tumor. After just a month of treatment (bottom), the tumor has shrunk dramatically.
Lecia Sequist
A clinical trial offers a first step toward personalizing cancer treatments.
For years, personalized medicine--the concept that treatments could be tailored to a person's unique genetic makeup--has been more buzzword than reality. One of the first diseases expected to benefit from a personalized approach is cancer, which appears in many genetically distinct forms. A new study led by Lecia Sequist, an instructor at Harvard Medical School and an oncologist at Massachusetts General Hospital Cancer Center , offers an initial demonstration that cancer treatment can be tailored to the genetic profile of a patient's tumor. In a small clinical trial published recently in the Journal of Clinical Oncology, patients with lung tumors were genetically screened to identify those likely to respond to a targeted therapy. Those receiving a drug matched to their tumor fared better than is typically seen with standard chemotherapy.
"It's really a giant step forward," says William Pao, a cancer researcher at Memorial Sloane-Kettering Cancer Center, who was not involved in the clinical trial. "The ultimate goal is to take a molecular fingerprint of someone's tumor and assign treatment based on molecular defects."
Standard cancer drugs are designed to preferentially kill cancer cells, but they can still be toxic to normal tissue. But cancer researchers have been working toward the goal of developing an array of drugs that could hit precise molecular targets in tumors, while being less toxic to normal cells. For example, non-small-cell lung cancer is an aggressive form of cancer that is typically treated with chemotherapy; however, in recent years, new drugs for the disease have been developed that target a specific molecule in cancer cells, called the epidermal growth factor receptor (EGFR). The drug examined in this study, Iressa, was the first EGFR inhibitor to come on the market in 2003, but its initial hype fizzled after larger trials showed that it did not lengthen survival for patients in the United States. Currently, EGFR inhibitors are used only after chemotherapy.
Increasingly, scientists have realized that cancers arise from different genetic mutations and have different points of weakness that might vary from person to person. Further research identified specific EGFR mutations in the tumors of a subset of patients that made them more susceptible to EGFR inhibitors. Many scientists have argued that the drugs could provide a greater benefit to these specific patients. In Sequist's trial, which was funded by AstraZeneca, researchers first screened patients with metastatic lung cancer for EGFR mutations and gave those with the mutations the option of receiving Iressa as a first treatment over chemotherapy. "This is a proof of concept," says Sequist. "We were trying to see if personalized medicine or genetically driven cancer therapy was feasible."
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Personalized Cancer Medicine Is Here, Now!
As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.
Findings presented at the Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that "functional profiling" with cell-based assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of "fresh" human tumors.
Cell-based Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell-based assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
Funtional profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.
As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
The funtional profiling technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a pre-test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Literature Citation:
Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
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