The next revolution in health care may be the dawn of “personalized medicine,” where a patient’s genetic makeup is taken into account when prescribing drugs and dosages. A sign of that coming era came over the weekend at an important oncology meeting, where the biotech company ImClone Systems announced that its colon cancer drug was not effective on about 40 percent of patients who have a mutated form of a cell-growth gene.
The trend towards personalized medicine will have repercussions for pharmaceutical companies, who are used to searching for the next blockbuster cancer drug that can benefit a vast number of patients.
Companies are beginning to accept a smaller market for some medicines in return for a better chance that those who use them will have a good result.
The interest reflects growing frustration over the limited number of patients who achieve a meaningful improvement in survival, despite the introduction of many cancer drugs in recent years. Although many of the new drugs target specific cancer genes, under current practice doctors administer these expensive targeted drugs without knowing whether the patient has the right type of cancer genes. Patients often undergo a hit-or-miss series of drug treatments to find one that works, an expensive and frequently uncomfortable process [The Wall Street Journal, subscription required].
These issues have been brought into focus by the ImClone drug Erbitux, which is used to treat both lung and colon cancers. At a meeting of the American Society of Clinical Oncology this weekend, ImClone researchers announced that Erbitux had no effect on about 40 percent of patients with advanced colon cancer. Those patients were found to have a mutated form of a gene called K-ras, which regulates cell growth and is believed to play a critical role in several cancers.
This suggests that oncologists should make sure their colon cancer patients are in the 60 percent with the standard form of the K-ras gene before prescribing Erbitux. The data “are pretty astounding,” says Eric Rowinsky, ImClone’s chief medical officer. He predicts that very soon all patients with colon cancer will be tested early on for kras status in the same way the breast cancer patients are tested to see their estrogen receptor status.
“We can now say scientifically there is no reasonable chance it will help” people with kras mutations, says Leonard Saltz, of Memorial Sloan-Kettering Cancer Center, who predicts that insurance companies will soon require a kras test for colon patients [Forbes.com].
Image: flickr/KB35
October 28th, 2008 at 1:37 am
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)
March 16th, 2009 at 5:40 pm
This is right here, in the present, not the future.