The Unfulfilled Promise of Genomic Analysis

In the March 8 issue of the New England Journal of Medicine, investigators from London, England, reported disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of chemotherapeutic agents.

As part of an ongoing clinical trial in patients with metastatic renal cell carcinoma (the E-PREDICT) these investigators had the opportunity to conduct biopsies upon metastatic lesions and then compare their genomic profiles with those of the primary tumors. Their findings are highly instructive, though not terribly unexpected. Using exon-capture they identified numerous mutations, insertions and deletions. Sanger sequencing was used to validate mutations. When they compared biopsy specimens taken from the kidney they found significant heterogeneity from one region to the next.

Similar degrees of heterogeneity were observed when they compared these primary lesions with the metastatic sites of spread. The investigators inferred a branched evolution where tumors evolved into clones, some spreading to distant sites, while others manifested different features within the primary tumor themselves. Interestingly, when primary sites were matched with metastases that arose from that site, there was greater consanguinity between the primary and met than between one primary site and another primary site in the same kidney. Another way of looking at this is that your grandchildren look more like you, than your neighbor.

Tracking additional mutations, these investigators found unexpected changes that involved histone methyltransferase, histone d-methyltransferase and the phosphatase and tensin homolog (PTEN). These findings were perhaps among the most interesting of the entire paper for they support the principal of phenotypic convergence, whereby similar genomic changes arise by Darwinian selection. This, despite the observed phenotypes arising from precursors with different genomic heritages. This fundamental observation suggests that cancers do not arise from genetic mutation, but instead select advantageous mutations for their survival and success.

The accompanying editorial by Dr. Dan Longo makes several points worth noting.  First he states that “DNA is not the whole story.” This should be familiar to those who follow my blogs, as I have said the same on many occasions.  In his discussion, Dr Longo then references Albert Einstein, who said “Things should be made as simple as possible, but not simpler.” Touché.

I appreciate and applaud Dr. Longo’s comments for they echo our sentiments completely. This article is only the most recent example of a growing litany of observations that call into question molecular biologist’s preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer “high price” genomic analyses for the selection of chemotherapy drugs should read this and related articles carefully as these reports portend a troubling future for their current business model.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

8 Responses to The Unfulfilled Promise of Genomic Analysis

  1. Linda says:

    Dr. N– How can RT ensure that the sample it has for testing has the most crucial mutations? Isn’t it plausible that the sample sent could totally miss the mutations that are most resistant to chemo? so the target becomes one set while the other set continues on in the body totally untouched by the recommended chemo?



    • All laboratory platforms are subject to “sampling errors”. That is, the tissue procured may not be reflective of the overall biology of the disease. This however is compounded by laboratory platforms that use FNA’s to measure genes or other “analytes” that are not functional parameters of the disease process, in all its complexity. These are instead mere reflections of the disease process, as it were, a veneer of information gleaned from the most superficial surface.

      To address smapling errors, we prefer large specimens which are assessed in their native state, not propagated or sub=cultured (thereby avoiding addtional artifacts). These are preferably obtained from metastatic sites, which often reflect greater degeees of resistance over the tumor primaries, giving us the best “shot” at both. We know from extensive clinical experience that many (most) patients that have responses to systemic therapy, have overall improvement with only a minority having true “mixed” responses. We also know that the tumors and their metastatic lesions share biologic similarities that provide useful insights into the tumor’s relative sensitivity to drugs. Even still, the subsequent re-growth of tumors, may reflect clonal expansion resulting from the elimination of the more sensitive tumors and emergence of a new dominant clone. To address this, we will often re-biopsy and re-dedicate our efforts to controlling the second or subsequent clones.

      All of these theoretical issues are hurdles to be overcome. They contribute to the fact that, although our lab analyses consistently double objective response rates, they are not perfect predictors. It is extremely important to remember that all the medical oncologists in practice today confront all of these same issues (heterogeneity, clonal divergence, differeing biology from primary to met, etc) yet they select drugs and combinations with absolutely no guidance whatsover!

      “In the land of the blind, the one eyed-man is king.”

      • It seems to me that this “intra-tumor heterogeneity” phenomena is not a new revelation to cell function analysis. Searching for these genetic predispositions 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.

        Testing of one sample of the tumor may well not render an accurate environment, unless you are recognizing the interplay between cells, stromal, 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.

        I think you were right, the complexities and redundancies of human tumor biology may have finally dawned on investigators who have clung to analyte-based molecular platforms. It is the capacity of functional profiling platforms to study human tumor microenvironments that distinguishes it from other platforms in the field, and offer predictive insight into the nature of an individual’s particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease.

  2. Annamaria Picollo says:

    My breast tumor early stage 1/grade 1 NO er/pr positive her2negative was tested using the OncoType DX show 8% recurrence rate, treatment AI for 5 years with radiation and lumpectomy.

    After reading my pathology report, three years ago, I raised the question as to why the whole tumor was not looked at after the lumpectomy to make sure the dx was the same through out the tumor. I was told it would be to lenghty, costly and I had nothing to worry about with my dx. That they only test a slice of the tumor and throw the rest away. I was taken back by his comment.

    After reading this article, am I to assume I may have been right? Or was the pathologist correct in telling me with his assessment of my tumor coupled with the Onco Type DX, things look good for me-I am not on the Titanic.

    This article is very depressing for someone who is 3 years out struggling with AI’s wondering whether or not the treatment was really what I needed.

    Even though three years have pasted, you comments would be appreciated.

    • There are always risks of “sampling error”. While we now know that cancers can take a long linear path to malignancy while others jump from beingin to malignant more quickly, most tumors are related to their ancestral stock with at least some defining features. It is hoped that the predominant biology of the disease will be provided by these prognostic markers, at least with greater accuracy than could be done wtihout them. You score is favorable and that is good thing.

  3. It’s a theoretical but overrated problem. The same problem applies to ER, Her2, EGFR mutations, KRAS, OncotypeDx. Even worse for trying to do studies on individual cells, e.g. as from circulating tumor cells. Less of a problem for cell function analysis, since they are sampling a much bigger mass of cells and are homogenizing the mass (actually homogenizing the distribution of microclusters).

    It’s analogous to the Gallup poll. You are projecting the behavior of a national electorate, based on a sample of 1,500 voters, who may or may not be representative of the whole. Rasmussen and Gallup have the same sized sample, but select different people for their polling (“likely voters” vs “all voters”), so their projections often disagree.

    It is one of the reasons why (1) “resistance” predictions tend to be more accurate than “sensitive” predictions (of the cancer is resistant anywhere, it pretty much doesn’t matter), if you use the “resistant” drug, the patient will have progressive disease and (2) the tests are more analogous to using the barometric pressure to predict for rain than they are analogous to a serum sodium level; i.e. the predictions are useful (assay “sensitive” drugs being seven times more likely to work than assay “resistant” drugs), but they aren’t perfect (i.e. 100%), no diagnostic test in medicine is.

  4. Robin Pointer says:

    My husband was diagnosed with pancreatic cancer a month ago. Sixteen days ago hehad a Whipple procedure, and it was determined that the cancer had spread to 7 out of 25 lymph nodes. We are to see an oncologist on Thursday about the next step. She suggested a clinical trial for a vaccine, along with gemzar. I don’t know if I like the idea of chemotherapy if we are trying immunotheropy. It seems to me that the chemo will break down his ability to fight the cancer from spreading. Everything I have read indicates that pancreatic cancer is very resistant to chemotherapy, so I am concerned about the protocol. Any suggestions? Please respond ASAP, as we only have a few days to make some very critical choices.

    • Despite pancreas cancers aggressiveness, the use of post operative chemotheapy (Gemcitabine) has provided real benefit. While some drugs are very immunosuppressive, Gemcitabine is not unduly so. If you receive Gemcitabine with or without the vaccine, it would seem that the therapy is either the “standard” or possibly something better. That is the question they seek to answer.

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