Genetics, genomics, targeted therapy, and “personalized” cancer care

If you are still under the illusion that, simply by identifying the precise structure of the deoxyribonucleic acid (DNA) of patients’ cancer cells, we will be able to develop and target drugs that can eliminate specific cancers (or indeed other disorders) in specific individuals, an article by Sharon Begley on the web site should help to disabuse you.

Ms. Begley’s article is derived from research just published in Science by Kresco et al. (“Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer“).

We all love it when science is really simple and straightforward (the e = mc2 model of science). Alas, most science isn’t that simple, and the biological sciences (or human biology if you want to be specific) follow complex sets of interacting scientific “laws” that make interpretation of how biology works extraordinarily difficult.

What Kresco et al. have been able to demonstrate in a very practical manner — and this does not come as news to many in the biological science community — is that cancer cells that are genetically derived from a single clone (and therefore have exactly the same genetic code) can behave in remarkably different ways over time. Why is this not news to many in the biological science community? Well, for one thing, we already knew that patients with identical genetic mutations can get utterly different clinical forms of cancer.

I have no intention of replicating Ms. Begley’s article here. She is an excellent science writer and I suggest you read her article for yourself. My only message is that the new paper by Kresco et al. is one more nail in the coffin of the idea that genetics alone will be able to drive targeted therapy for personalized medicine. It was never true to begin with and it is certainly not true today. At best genetics can be provide diagnostic, therapeutic, and prognostic opportunities for definable subsets of patients. Other factors (many still to be identified) will profoundly impact whether a specific cancer with a specific genetic profile is or is not effectively and safely treatable in specific patients whose cancer carries that genetic profile.

4 Responses

  1. We are up against diseases of the metagenome. Our entire community of living organisms within each of us makes the proliferation and growth of these diseases so complex and unique, it’s hard to imagine any “one size fits all” solutions emerging. This video contains interesting perspectives but it is in the context of another disease.

  2. The bestseller The Emperor of all Maladies: A Biography of Cancer by Siddhartha Mukherjee is a fascinating read about the “War on Cancer” and the various times, over the last 75 years, when the research community thought they were on the verge of being able to defeat cancer once and for all. This book requires no background medical or scientific knowledge. Reading the book will certainly temper (but not completely kill) hope of finding a definitive cure for cancer.

    A number of the new cancer prognostic tests, and companion diagnostic tests are not based on DNA sequences, but rather on a genetic expression profiles (or signatures). This is an analysis of the proteins being produced by the cancer cells, and may (or may not) prove to be a somewhat better indicator of how the cancer cells are actually behaving.

  3. What you say is somewhat true but to deny that knowing an individual’s (better yet a population’s) genetic code will not help in the designing or implementation of drugs simply neglects basic facts. For instance, mutation X for a patient with breast cancer will result in drug Y not working. Or mutation X in specific pathway should make this person’s cancer more susceptible to a specific drug. We’re not even at the point where we know all the variations of alleles in the greater population and how that might affect drug development. The point you nail is that other factors affect disease besides purely genetic ones. For instance, epigenetics, environmental issues, etc. Regarding your point about single clones from a cancer cell, it is my understanding that cancer cells are particularly susceptible to mutation.

  4. Dear Grosenfeld:

    No one is denying the value of genetic data … However, many people have massively over-estimated the degree to which knowing the genetic code of specific people, populations, and cancer cells would “inevitably” lead to effective personalized medicine.

    Genetic data are just one of many tools toward a therapeutic end, and (as I had originally pointed out and you have repeated) their primary value is diagnostic and prognostic rather than actually therapeutic. If we know that a specific set of people have a specific prostate cancer gene, it may help us to treat them. However, I think I can probably make a safe guarantee today that just because we have a specific treatment that is effective in treating the prostate cancer of a man with a specific mutation to his prostate cancer (a prostate equivalent of the HER2/neu gene in breast cancer, for example), will not mean that that therapy is effective in all men with prostate cancer and that gene (or even, necessarily, most of them).

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