Posted: October 10, 2014

Gene mutations have been thought to be key to an understanding of cancer.  In a blockbuster article that got almost no notice, doctors from Harvard Medical School (Dana Farber Cancer Institute mostly) and the Broad Institute at MIT (named after Eli Broad, an extraordinary philanthropist from LA) announced that they had figured out why a cancer drug that shouldn’t have worked did so, and why it stopped working when it did. The article was published as a “Brief Report” in the New England Journal of Medicine on October 9, 2014.  Click here for a link to the abstract.  Dr. Stark can provide the entire piece if requested, but can’t create a link to it because of copyright issues.   Here are the details: an unfortunate patient presented to the Farber with rapidly progressive anaplastic thyroid cancer.  He should have died promptly because there is no known effective treatment.  The patient was treated with everolimus, a drug designed to inhibit a gene called mTOR, which conveys growth advantage and metastatic potential to tumors when it is activated as part of a larger trial to treat lots of different patients with this drug to see what it would do.  Nearly miraculously almost all the cancer disappeared for 18 months.  Then it came back.  Here is what is so important: the doctors took tumor samples from before and after treatment with everolimus and did complete genetic sequencing.  They found a mutation in TSC2 a gene that regulates mTOR before treatment.  After treatment that mutation was still present but mTOR was mutated in such a way as to create a three-dimensional hindrance to the entrance of everolimus into the protein product of mTOR.  Hence the reason why the drug stopped inhibiting the tumor stimulating properties of the gene.  Another drug not dependent on the same three-dimension lock-and-key arrangement at the same site, continued to inhibit mTOR.  The authors don’t state whether that drug was approved for human use and whether their patient received it.  If not one can safely assume that he died quickly.  Dr. Stark weighs in: this brief report — so brief that the age, gender and outcome of the patient were left out — shows the promise of molecular biology in the treatment of cancer.  Soon all newly diagnosed cancers will be sequenced and treatment will be guided by mutations, not site of origin.  The basis for drug resistance — previously the subject of intense interest and speculation — is now understood at a molecular level.

Update 2020: the total DNA sequencing of newly diagnosed cancer is becoming routine at major cancer centers.  The cost has come down to about $1000 and the turnaround time is a day or two.   More and more treatments are being guided today by the mutations found rather than by where the cancer originated.  Such mutations as microsatellite instability, formerly thought to occur only with colon cancer, and a determinant of therapy, is now being reported much more widely — including cancers of the biliary tract, uterus, bone (osteosarcoma) and thyroid.  When tumors from these sites express microsatellite instability, drugs such as pembrolizumab work well when they would not be expected to work at all.   This is a rapidly evolving field.  More to come….