Simply finding a mutation
The idea of simply finding a mutation and then pick an appropriately targeted drug seems like a nice idea. However, not every key that looks like it will fit a lock will actually turn it. The same is likely to be the case with targeted drugs. There are numerous common mutations in various tumor types, but they don't know that all those mutations are going to turn out to be relevant, as many of them are essentially bystanders.
Gene mutations are changes in a genomic sequence, the DNA sequence of a cell's genome. These random sequences can be defined as sudden and spontaneous changes in the cell. Sequencing is a laboratory process that determines the nucleotide sequence of DNA (can involve the whole genome or whole exome or be targeted to as little as one coding sequence). A genome is the complete set of genetic material. An exome is part of the genome formed by genes that code for proteins and other functional gene products (known as exons).
Gene rearrangement is a structural alteration of a chromosome that causes a change in the order of its loci. The carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. DNA rearrangements are known to occur only in cancer cells and not in non-cancerous cells, making them fit to be tumor markers for cancer. The incidence of ALK gene rearrangement in patients with NSCLC is in the range of 2-4 percent, ROS1 gene rearrangement in the range of 1-2 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events.
Why don't all the mutation positive patients respond and why do some mutation negative patients respond? Cancer biology is complex. Molecular biologists can only seek and identify that which they know about from earlier (a priori). What happens if you have MEK, ERK, SHH, LKB1, FGFR, PI3K, etc.? There are numerous mutations, insertions and deletions. A gene mutation, deletion, translocation or amplification could disrupt many cell functions, leading to drug resistance, or could inactivate or damage the doors through which a drug enters a cell.
Lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype-phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.
It isn't just molecular analysis, it is whether the capacity to judge phenotypes will be easily achieved at the genotype level. Systems biology suggests that the simple knowledge of a gene's presence or absence does not confer a biological behavior. Biology is not linear.
The real question that should be asked is whether Tarceva would work on your individual cancer cells, not whether you have the ALK gene or the EGFR gene or some other rearrangement. The answer is that Tarceva can work for any lung cancer patient, or not. It's a question of whether your individual cancer cells are "sensitive" to Tarceva or are they "resistant" to Tarceva, regardless of the gene your cancer cells "hang" with.
To learn more about this:
Chasing Gene Mutations
Tarceva Delivers Benefits Across Broad Range of NSCLC Patients
The Role of Genomic Testing for Predicting Response to Targeted Therapy
The Problem with KRAS Mutation Studies
Gene Expression Signatures Not Ready for Prime Time
Anti-Angiogenic Activity and VEGF Pathway Inhibition of Tarceva
Gene Mutation vs Chromosomal Theory of Cancer
Targeted Therapy is Still Trial-And-Errot Treatment
Functional Profiling to Select Chemotherapy in Advanced NSCLC