Personalized medicine figures large in the clinical management of many types of cancer. The example I struggle to keep up with is the ever-changing algorithm for treating breast cancer, where mutations, tumor markers, sentinel lymph nodes and receptors all play a role in treatment planning. Now another paradigm shift may be necessary with the publication of a study on "tumor heterogeneity" in the New England Journal of Medicine. As Rick and I agree in this week's podcast, and as we illustrate in the YouTube, this heretofore unrecognized factor may explain much of cancer's seemingly fiendish ability to sidestep even the most elegantly targeted treatments.
What exactly, then, is "tumor heterogeneity?" Simply put,this is the range of genetic aberrations found in a tumor. These have been seen before, both within a single tumor and between tumors of the same type, say, one man's prostate cancer versus another's. But now, variation has been characterized in different tumor sites in the same patient.
The study examined, using a multitude of methods, kidney cancers from 4 patients. All of the patients had metastatic disease, and tumor biopsies were retrieved from more than one site. Additionally, biopsies were obtained and examined both before and after treatment was initiated with everolimus, one of the few treatment options for this disease.
The study found that only a minority of the mutations and genetic aberrations found in the tumor were reflected in a single biopsy specimen. In plain English, the tumors from different areas of the body were more different than they were alike! Yikes! If we're basing therapy on the presence or absence of a specific mutation or mutations identified from a single biopsy specimen, we're really only targeting part of the disease, and the least part at that.
The authors also look at whether therapy, in this case with everolimus, precipitated the mutations and/or heterogeneity. The short answer is no, the cancers appear to develop this way, perhaps as a survival strategy. They did find, however, that during the development of the tumor, a common 'trunk' was present for some time, eventually giving way to branches that diverged and expressed differing genetic changes. They suggest that finding those common aberrations and targeting the trunk is one strategy that may bear fruit clinically.
Obviously, one short term strategy likely needs to involve biopsying multiple sites in patients with metastatic disease in order to identify a more complete range of the mutations present in their tumor. One place this may have immediate impact is in use of agents known to be beneficial only when certain mutations are present, and that may be harmful when they are not. Venurafenib for metastatic melanoma springs immediately to mind.
Other topics this week on PodMed include use of opioid medications in veterans in JAMA, disturbing news about Clostridium difficile infection in MMWR, and two medications used in Alzheimer's disease- should you switch? also in NEJM. Until next week, y'all live well.