Tacky Genes Give Me the Blues

DUSP6! MMD! STAT1! ERBB3! LCK!

Was ist diese? CB radio patter? Pilot to co-pilot chatter? 3rd-and-long huddle banter?

Of course not - that would be too easy. These cryptograms represent five different genes found within non-small cell lung cancers (NSCLC) that predict the both the relapse-free and overall survival of patients at the Taichung Veterans General Hospital in Taiwan who underwent surgical removal of early stage NSCLC, as reported in this week's New England Journal of Medicine.

By the way, if you've ever wondered why scientists use so many acronyms, here's a good example. The real names of the genes mentioned above are dual-specificity phosphatase 6 (DUSP6), monocyte-to-macrophage differentiation-associated protein (MMD), signal transducer and activator of transcription 1 (STAT1), v-erb-b2 avian errythroblastic leukemia viral oncogene homolog 3 (ERBB3), and lymphocyte-specific protein tyrosine kinase (LCK). As Max Born would say (if he were still alive and not so obsessed with the Matrix), "Nicht ist das erstaunlich?"

This is not the first study to show that the expression of certain genes within lung tumors portends a worse prognosis. It is the first study to use a signature of only five genes to produce a statisically meaningful correlation between their expression and survival of the patient. (A collection of poor prognosis genes is called a high-risk gene signature).

The scientists analyzed tumor samples from 125 patients with differing stages of lung cancer and found 16 genes that seemed to raise or lower the odds of recurrence or death. Further analysis narrowed this to five genes that formed a signature of risk. They tested this signature on half of the samples and found a strong correlation to how well the patients fared. Median survival was 40 months for the lowest-risk group and 20 months for the highest-risk, according to the strength of activity of the five genes. The median time until relapse also was significantly longer -- 29 months versus 13 months -- for the lowest-risk group.

The reason this study is important is because of the fact that several clinical trials have shown patients with resected NSCLC who receive post-operative adjuvant chemotherapy have superior long-term survival compared with observation only. In the Taiwanese population, though, stage I lung cancer patients with a low-risk gene signature had an actuarial three year survival of 90% compared with only 38% for those with a high-risk gene signature. If we had the results of these assays would we still recommend chemotherapy to patients with such a good prognosis? Does adjuvant treatment have any salutary effect if given to patients with the high-risk gene signature? Can community oncologists like myself order this test as part of the routine analysis of a lung cancer specimen?

To put it in the vernacular, "These is the questions, dude." They are tough questions but I believe they will soon be answered; too much is at stake to stop now. As Professors Herbst and Lippmann from The University of Texas M.D. Anderson Cancer Center state in the accompanying editorial:

It is now crucial to create molecular tools that can predict the response of cancers to single agents or combination chemotherapies, in order to guide the development of new drugs or improve routine clinical care... patients with early-stage cancers will be assigned to particular drugs on the basis of the molecular characteristics of the tumors. Then the development of drugs for the treatment of lung cancer will be focused on personalized therapy.

Like a butterfly emerging from its chrysalis, the future of cancer care reveals itself slowly, ever so slowly, but surely as a metamorphosis of wonderment. May all who long for this maiden flight to begin be blessed with determination and hope.

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You asked the question about whether or not you would/could order the tests for these 5 genes (or any other list that happens to emerge from the literature). I think an additional question to ask is: Are these kinds of tests useful? Would you not provide as aggressive treatment to someone who only has a 38% chance of long-term survival? Or even 5% or 1%? How do you know they will not be one of the few that survives?
I agree that it will help in the long-run, but I think these studies (similar report recently came out in Nature Genetics and the established "profile" for breast cancer) raise many additional issues about utility and influence in decision-making.

I hope these tests will be extremely useful. When my dad was receiving treatment for NSCLC, he tried four different types of chemo. If we had known the gene signature of his specific cancer, we might have been able to immediately identify the chemo regimen most likely to be beneficial without the trial and error. The more personalized cancer treatment becomes, the better chance the patient will have.

And yes, I do think it's fair for a doctor and patient to know the statistics regarding their long-term survival when making treatment decisions. If the patient wants to shoot for being in that 1%, let them go for it. On the other hand, some might understandably forgo chemo if they know how slim their chances are.