This is my first attempt at typing a blog on my iPad, so we will see how it works out. It would certainly be nice not to have to lug my laptop around with me on my travels.
I have read an article recently that has altered my view of the cancer world, which I hope you will find interesting. It was published several months ago in Nature by William Lee and colleagues (Nature vol. 465, pp 473-77) entitled "The mutation spectrum revealed by paired genome sequences from a lung cancer patient." The investigators used next-generation sequencing technology to compare the complete sequences of a primary lung tumor and adjacent normal tissue. The results are stunning, and if they are in any way representative they suggest we face daunting challenges in the cure of this and other smoking-related cancers.
The research demonstrated an astonishing number of mutations. Just to give some flavor of this, the tumor "harbors an activating point mutation in KRAS as well as copy number gains for SHC1, GRB2, SOS, ARAF, MAP3K3 and ELK1, suggesting that there are at least eight potentially activating genetic lesions within this particular pathway." And that is just the beginning: the tumor had multiple other pathways known to be drivers of tumor growth present as a result of mutational events.
Because the patient's smoking history was available, as well as a measure of the total number of mutations present in the tumor, the authors calculated that the tumor harbored one mutation for every three cigarettes smoked. Just astonishing, and frightening as well. Lung cancer seems to be segmenting out into two categories in the clinic, and these data explain why. Nonsmokers with lung cancer are likely to have tumors treatable with drugs that block EGFR or ALK, with high response rates and relatively long progression free survival. Smokers have cancers that rarely respond to these agents. Think of them as "dumb tumors" and "smart tumors." Dumb tumors tend to have a single or a few molecular drivers (think CML and GIST), whereas smart tumors have accumulated bunches of mutations over a lifetime of carcinogen exposure.
The smart tumors will probably require assaults from multiple targeted biologics, and it is quite possible that two lung cancer patients may require very different inhibitors. If this is true of lung cancer, it is likely true as well of other “smart tumors.”
How do we develop combinations of targeted therapies for patients with smart tumors, when we work within a clinical trials system that demonstrably is anything but smart? How do we identify the right patients for the right combinations in a timely fashion when common cancers become orphan diseases with orphan sub-diseases? How do combination therapies get approved or even tested when every patient becomes a bioinformatic and regulatory minefield? This a huge challenge, though one we must address. And it is not just a scientific issue; addressing the science will require a different clinical trials development and approval apparatus. The current regulatory apparatus was developed in a different (and simpler) era. It is in serious need of a systematic overhaul, one that would simplify, harmonize, and improve efficiency while maintaining just concerns regarding safety and privacy. But it also may need an overhaul that takes the new reality of “smart tumors” into account.
On an unrelated note, it isn't too late to vote for the ASCO election. Please vote! We want your society to be truly representative of its members.