Vermaat and colleagues from the University Medical Center Utrecht, Hubrecht Institute, Utrecht, The Netherlands, and Hoffman-La-Roche Inc./Genentech, Nutley, New Jersey, recently showed that there was significant genetic variation between individual primary colorectal cancer tumors and their subsequent respective hepatic metastases. As stated by the authors, “In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters.”
In their study, primary colorectal cancer tumors and their matched hepatic metastases were analyzed by targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material from 22 patients. A total of 817 gene variants that potentially altered protein function were identified. Compared with the individual primary tumors, an average of 83 potentially function-impairing gene variations were gained and 70 variations were lost in the respective metastases.
Implications for Targeting Metastases
Identified variations that could potentially influence response to therapy included novel and known variations in such genes as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, as well as aberrations in the upstream and downstream genes of EGFR/PI3K/VEGF pathways and other pathways (eg, mTOR, TGFβ). Samples from 11 patients who received chemotherapy between removal of the primary tumor and metastasis did not exhibit an increase in the amount of genetic variation.
As noted by the investigators, the central implication of these findings is that “the choice of treatment in studies investigating targeted therapies [in metastatic disease] should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.” ■
Vermaat JS, et al: Clin Cancer Res 18:688-699, 2012.