Friday, June 3, 2011
Using Genomics to Improve Treatment of Lung Cancer
Recently the treatment of lung cancer has advanced considerably as a result of genomic analysis of the tumor and the development of targeted drugs. Lung cancer is divided into a number of different categories based on the microscopic appearance under the microscope. One type is called small cell and the others are usually “lumped” together as “non small cell” lung cancer because the former is treated much differently than the latter group. The non small cell lung cancers can be genomically evaluated to determine if there are certain common genetic mutations such as KRAS, EGRF, MEK and other mutations or the EML4-ALK translocation.
Patients with the EML4-ALK translocation respond reasonably well to the tyrosine kinase inhibitor crizotinib (somewhat similar to the one used for CML). As with the translocation seen in CML, this is a fusion gene that occurs during a translocation of two parts of two chromosomes that lead to a portion of the normal EML4 gene being fused next to the normal ALK tyrosine kinase gene. When this happens the new gene transcribes a variant tyrosine kinase protein which leads in part to the development or progression of lung cancer. Studies to date indicate it to occur mostly in the subtype called adenocarcinoma, in those with prior treatment, in younger patients and those who have no or a minimal smoking history. Although this represents just a small subset of all lung cancer patients, treatment of them in a Phase 1 trial with crizotinib resulted in a confirmed response in 57% (47 of 82) of patients with another 33% (27 of 82) having stabilized disease. [Kwak et al, New England Journal of Medicine, Oct 28, 2010] Although not a randomized trial, it is well known that most second line treatment regimens have no better than a 10% response rate so this would appear to be a breakthrough of sorts. Certainly it is not a panacea, nor a cure. But with minimal side effects these patients received some useful benefit and probably will have a lengthened survival Further studies will need to be done but if it is correct that about 5% of lung cancer patients have this fusion gene, then about 9000 patients per year would potentially benefit form crizotinib or similar ALK kinase inhibitors. Concurrently, one would not choose to use this drug in patients without this fusion gene and its abnormal protein. It also appeared that some patients had a further mutation such that crizotinib was not effective in them. [Note: Crizotinib is not yet approved by the FDA so access to the drug is via clinical trials.]
Patients who have the EGRF mutation appear to be distinct from those who do not as to response to the drugs erlotinib (Tarceva) and gefitinib (Iressa). EGRF is a tyrosine kinase that when mutated appears to play a role in lung cancer development and progression. Those who do have this mutated gene and its transcribed protein will respond to these two drugs in about 70% of cases with progression free survival of about a year and total survival of about two years. This would appear to be superior to standard drug therapy used today. Without this mutation, the patient will do much better treated with chemotherapy. So the treatment of a new patient with lung cancer today should include genomic analysis of the tumor so that the patient can receive the most appropriate first line treatment and then reanalysis later to determine if there are further mutations or translocation that would direct second line treatment options.
This is just one more example of how genomics is making medical care more custom-tailored, one of the five key medical megatrends.
Praise for Dr Schimpff
The craft of science writing requires skills that are arguably the most underestimated and misunderstood in the media world. Dumbing down all too often gets mistaken for clarity. Showmanship frequently masks a poor presentation of scientific issues. Factoids are paraded in lieu of ideas. Answers are marketed at the expense of searching questions. By contrast, Steve Schimpff provides a fine combination of enlightenment and reading satisfaction. As a medical scientist he brings his readers encyclopedic knowledge of his subject. As a teacher and as a medical ambassador to other disciplines he's learned how to explain medical breakthroughs without unnecessary jargon. As an advisor to policymakers he's acquired the knack of cutting directly to the practical effects, showing how advances in medical science affect the big lifestyle and economic questions that concern us all. But Schimpff's greatest strength as a writer is that he's a physician through and through, caring above all for the person. His engaging conversational style, insights and fascinating treasury of cutting-edge information leave both lay readers and medical professionals turning his pages. In his hands the impact of new medical technologies and discoveries becomes an engrossing story about what lies ahead for us in the 21st century: as healthy people, as patients of all ages, as children, as parents, as taxpayers, as both consumers and providers of health services. There can be few greater stories than the adventure of what awaits our minds, bodies, budgets, lifespans and societies as new technologies change our world. Schimpff tells it with passion, vision, sweep, intelligence and an urgency that none of us can ignore.
-- N.J. Slabbert, science writer, co-author of Innovation, The Key to Prosperity: Technology & America's Role in the 21st Century Global Economy (with Aris Melissaratos, director of technology enterprise at the John Hopkins University).