We are about to undergo a major change in tumor genotyping for cancer patients, possibly even before the basic protocol is broadly adopted. Not only will the genotype of a tumor be required to initially determine appropriate chemotherapy (see: Identifying Therapeutically Relevant Genetic Abnormalities in Cancer Patients) but the process may need to be repeated multiple times subsequently (see: One Biopsy Not Enough to Reveal Genetic Landscape of a Tumor). Below is an excerpt an article that addresses this topic:
A small study that shows a surprising complexity of genetic changes within a single tumor has far-reaching implications for the march toward personalized cancer therapy....A single biopsy from a tumor might not be sufficient to give a full picture of its genetic landscape [according to a recent study]. When the researchers examined 10 biopsies taken from a single kidney cancer, they found "an extraordinary amount of diversity" in the genetic changes that had taken place in different parts of the tumor....The [research] team also found differences in genetic changes between the primary tumor and metastases that developed both locally and at a distant site (in the chest wall). Similar findings have been documented by other research groups, but it is the extent of intratumoral heterogeneity that is surprising....The findings have far-reaching implications for the efforts currently being directed toward personalized cancer therapy, in which therapy is targeted at genetic changes identified in tumor tissue. An example of this is the SnaPshot broad genetic screen program being used in routine clinical practice at the Massachusetts General Hospital in Boston.
Here's more about the SnaPshot program (see: Screening: Smile, they're taking a SNaPshot of your cancer-causing genes):
Personalized cancer treatment is just around the corner, suggests a new study. Using SNaPshot, a “multiplexed, robust, highly sensitive and quick clinical test,” [researchers] at Massachusetts General Hospital have screened patients with non-small-cell lung cancer (NSCLC) for multiple cancer-causing gene mutations and demonstrated that implementing broad genotyping in routine clinical practice can identify the right type of treatment for the right patients.
In this emerging era of personalized medicine and the need to match patient chemotherapy to the genomic profile of a tumor, we are now coming to better understand the genetic intratumoral heterogeneity, to quote a phrase from this article. Cellular genetic characteristics appear to change over time and a single, initial biopsy of a tumor may provide insufficient information to guide treatment long-term because of this heterogeneity.
My first thought about how to address this problem was to examine circulating tumor cells (CTCs) (see: Circulating Tumor Cells for Assessing Survival in Pancreatic Cancer Patients). However, this approach will probably not suffice, even if this technology were sufficiently mature. I suspect that the metastasizing, circulating cells are genetically different than their parent cells. In fact, it may be these genetic differences that determine these cells' ability to circulate and implant in distant organs. The only "practical" solution that I can conjure up in the long run is for continuous genetic monitoring of a tumor using molecular imaging. I say "practical" here because this technology is still largely confined to research labs.
In the short-term, we will need to be satisfied with periodic sampling of tumor tissue using standard biopsy techniques combined with genetic analysis to determine which chemotherapeutic agents will be most effective. Recall, however, that there is some morbidity associated with obtaining a tumor biopsy, even with fine needle aspiration (FNA). However, it must also be stated that two of the most common types of tumors (GI and breast) are accessible via endoscope or percutaneously (see: Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review).
This "intratumor heterogeneity" issue is not a new revelation to cell function assaysts. As you can see, searching for these genetic predispositions, it is like searching for a needle in a haystack. One can chase all the mutations they want, because if you miss just one, it may be the one that gets through. Or you can look for the drugs that are "sensitive" to killing all of your cancer cells, not theoretical candidates.
Contrary to anlayte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform. By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.
Testing of one sample of the tumor may well not render an accurate environment, unless you are recognizing the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. The human tumor primary culture microspheroid contains all of these elements. Studying cancer response to drugs within this microenvironment would provide clinically relevant predictions to cancer patients. It is the capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.
They have observed some degree of "genetic drift" where mets tend to be somewhat more resistant to drugs than primaries. Over the years, they have often encouraged physicians to provide nodal, pleural or distant site biopsies to give the "best shot" at the "most defended" of the tumor elements when metastatic disease is found.
The tumor of origin (as in the NEJM study as well) and the associated mets tend to retain consanguinity. That is, the carcinogenic processes that underlie the two populations are related. This is the reason they do not see "mixed responses" (one place in the body getting better and another place in the body getting worse), but instead, generally see response or non-responses.
Heterogeneity likely underlies the recurrences that are seen in almost all patients. This is why they try to re-biopsy and re-evaluate when recurrences are observed. Heterogeneity remains a theoretical issue no matter what platform one uses. Why complicate this fact by using a less biologically relevant method like genomics that only scratches the surface of the tumor biology?
Posted by: Gregory D. Pawelski | March 12, 2012 at 01:43 PM