Genome Technology’s Daily Scan picked up a very interesting article from the Boston Globe on personal genetic screening of cancer patients, which is to begin within the year at Massachusetts General Hospital. Their plan is to screen tumors of 5000-6000 cancer patients for 110 mutations in 13 key cancer genes. This is an important step for personalized medicine, and also, something that we should have been doing a long time ago.
Why All Tumors Should Be Genotyped
Despite the reluctance of some clinicians to rely on genetic information for personalized treatment, and the reluctance of most insurance companies to pay for it, the body of evidence supporting personalized genetics-driven cancer treatment is substantial. The Boston Globe article cited one anecdote about a woman diagnosed with lung cancer who wasn’t responding to surgery and chemotherapy. A genetic test revealed that the tumors were positive for EML4-ALK, a transforming fusion gene identified in 2007. Luckily, a pharmaceutical company was testing a drug that targets the fusion protein.
Another anecdote supporting personalized cancer treatment was told at AGBT 2009 by Marco Marra. They’d had an 80 year old male patient with papillary adenocarcinoma, a tumor of unknown origin that was found on his tongue. He underwent surgery, but after 4 months there were lots of lung metastases (he showed a PET-CT). The tumors had EGFR amplifications but didn’t respond to erlotinib, an EGFR inhibitor. Light transcriptome sequencing revealed some clear genomic alterations in the PTEN/RET pathway (PTEN was lost, RET was activated, but not mutated). Long story short, they treated the man with the renal cell carcinoma drug sunitinib, a tyrosine kinase inhibitor that targets RET, and the patient’s response in just a few months was near miraculous.
So Mass Gen is screening 13 genes in every tumor. I’d hoped to learn which genes/mutations were being screened, and the equipment that will be applied, but unfortunately the Boston Globe article was sparse on the details. (Please, post a comment if you have any). I could make some educated guesses: EGFR, KRAS, RET, TP53. Yet 13 genes seems like a rather paltry number, considering the number of new cancer genes being identified by large cancer sequencing projects.
Who Pays for Genetic Testing?
Of course, I admit that genetic testing can be expensive, and the fact that insurance companies are already balking makes this a serious concern. From the article:
"...representatives of the state's three major health plans said they pay for gene testing only when it has proven medical benefits, meaning insurers may balk at paying for some of the new testing."
As expensive as some of these cancer drugs are, one would think that insurance companies would be all for testing patients a priori to pick the best one. With the rapid advance of DNA technologies, it won’t be long before genetic testing is a lot cheaper than chemotherapy, and maybe then the insurance companies will come around.
Systematically Correlating Mutations with Drug Response
In the meantime, it looks like we have to go out and prove the medical benefits – that means screening large numbers of patients, and cross-referencing their mutational profiles with how they respond to treatments. I wonder, can we test something like this in vitro – culture cells from various tumors, characterize their mutations in a number of genes, and then throw various cancer drugs at them. Compare the mutations to the drug response, especially for known drug-target pairs, and you could rapidly build a cancer pharmacogenetics database.
High Interest in Fusion Genes / Fusion Proteins
It’s curious to me that the woman with lung cancer had a recently-identified gene fusion, and the drug company (ta-da!) already had a drug in trials that targets it. Fusion genes seem to be a hot topic – especially those that involve protein kinases, like the well-known BRC-ABL fusion in leukemia. It seems like we should be finding lots of these, and if they make good drug targets, so much the better.