Cancer Survivors Network

Sorry that you're going through this situation. I wanted to share with you some info about my own wife. She's 51 and was diagnosed with stage I lung cancer with a KRAS mutation in September 2009. She went through the first round of chemo with carboplatin and vp-16(etoposide). In January 2010, she went from stage I to stage IV resulting in metastatic cancer in her bones. The initial chemo did not work. I took her to MD Anderson Cancer Center in Houston. They gave us some second line drug options to give to our doctor at home. One of the options was something called Alimta (Pemetrexed). My wife took two rounds of this drug once every three weeks. The doctors checked the PET scan from Houston against a scan that we had done at home in Charleston, SC. We were happy to see that no new cancer had developed and the existing spots had not changed. She will continue on Alimta and add in Carboplatin next week. We're hopeful that this keeps working. Don't give up. My advice is to ask for a scan in the middle of chemo to make sure that what she's getting is working.

What they would be testing for is to see if you have the EGFR protein (the "wild type" version KRAS). It may be able to tell you whether or not your cells are potentially susceptible to this mechanism of attack. However, it cannot tell you if Erbitux will work for "your" individual cancer cells. It is still a "trial-and-error" approach as conventional chemotherapy is. It will not be able to tell you if Erbitux, or some other inhibitor drug would work better. Or if Erbitux would work better when in combination with a conventional drug or another targeted drug.

Although Tarceva and Erbitux kill cells containing a normal but overactive EGFR (epidermal growth factor recpetor) molecule, only small molecule Tarceva kills lung cancer cells containing a mutated EGFR molecule. The monocolonal antibody (large molecule) drug Erbitux has little effect on the mutant signal, because it strikes at a different part of the EGFR molecule. It involves a normal, not mutant, EGFR molecule.

While those with EGFR mutations would benefit from Tarceva, others without EGFR mutations would benefit from Erbitux. In this setting, to inhibit the mutant receptor, you need to inhibit the domain of the EGFR molecule that lies within the cell, as opposed to the domain that lies outside the cell.

Sometimes targeted drugs can be used, but they can never find the correct one for the "individual" patient by using molecular tests (they never even test the drug against the tumor cells). Most times, targeted drugs need to be used with conventional cytotoxic chemotherapy. Sometimes they can find a combination of targeted drugs that may work.

What is still not understood by purveyors of the Cancer Genome Project is that the original Human Genome Project dealth with a homogeneous population of normal diploid cells. This is different from primary tumors, which are heterogeneous and have a genomic signature unique to every patient.

Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways - network of genes - of tumor cells can be known in sufficient detail to control cancer. Each cancer cell can be different and the cancer cells that are present change and evolve with time.

It was thought that if billions of dollars were poured into genotyping by DNA sequencing of primary tumor would find the critical mutations that cause cancer and then make drugs to them so that each patient can have a unique treatment.

The major problem with this is the primary tumor is so heterogeneous that each cell within it is likely to have a unique genomic signature at the level of mutations, as well as at the level of gross genomic imbalances and methylation signatures.

And the cells that will be dangerous to the health of the patient and depart to other organs make up only a minute fraction of the tumor. They are also genomically different to the cells in the primary tumor.

Which of the millions of mutations, methylation changes, and gemomic imbalances are in the cells that leave the primary tumor? This cannot be ascertained by bioinformatic and statistical methods. It involves isolating the cells that depart.

Also, which of the genomic alterations that are in the departing cells will be instrumental in the process of subsequent metastatic growth? Most of the cells that leave home don't survive the journey in the blood or lymph systems, and many cancerous cells that eventually do lodge in a distant organ simply remain dormant.

It would seem more prudent to invest in the development of diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize.

When the front-line treatment for solid tumors is still chemotherapy (cytotoxic or targeted) and radiation, and the best that blockbuster drugs can achieve is to prolong the inevitable by either a few months or not at all, then it's surely time to look outside the box.

Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process.

A number of cell-based assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms. They have the database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms.

Two of them have the most extensive experience in this field. What they do is a technique called "functional profiling," capable of examining the nuances of cellular response to drugs. It looks at the entire genome, not just an individual (or a few) genetic mutation mechanism.

Reference:

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)

which mutation do you have?  is it solid or ground class...i would like to communicate with anyone who also has the non wild

does your wife have the non wild KRAs? is so,can you share what is her treatment..