Genetic Variations and Treatment Outcomes in Esophageal Cancer

http://www.medscape.com/viewarticle/705254
Maurie Markman, MD
Authors and Disclosures
Published: 07/12/2009

Genetic Variations in the PI3K/PTEN/AKT/mTOR Pathway Are Associated With Clinical Outcomes in Esophageal Cancer Patients Treated With Chemoradiotherapy

Hildebrandt MAT, Yang H, Hung MC, et alJ Clin Oncol. 2009;27:857-871
Summary
Investigators at the MD Anderson Cancer Center in Houston, Texas, conducted a retrospective review of 210 patients with esophageal cancer treated with chemoradiotherapy followed by surgical resection, or treated with induction chemotherapy followed by chemoradiotherapy and surgery. Their goal was to determine whether the presence of particular common genetic variations within the PI3K/PTEN/AKT/mTOR cell signaling pathway affect response to treatment, risk of recurrence, or overall survival.This critically important pathway had previously been shown in a number of tumor types to be important in the risk for and rate of progression of cancer, and to play a role in chemotherapy resistance.

The analysis conducted by these investigators revealed several genetic variants within this pathway that are significantly associated with an inferior (AKT1, AKT2) or a superior (variants of PTEN) treatment outcome. Of note, the adverse effect on outcome was increased with the greater number of unfavorable genotypes identified within an individual patient's cancer, resulting in rates of recurrence-free survivals within particular genotype subgroups ranging from 12 to 42 months.
Viewpoint

The striking findings in this retrospective analysis reveal the potential critical importance of specific genetic variations within the PI3K/PTEN/AKT/mTOR pathway in patients with esophageal cancer. Specifically, these variations can be used to help define inherent resistance to certain chemotherapeutic agents and radiation, and affect the ultimate outcome of a particular therapeutic strategy.If the results of this analysis are confirmed by other investigators in independent esophageal cancer patient populations, testing for genetic variations in this pathway might prove a novel and realistic approach to prospectively determining disease management in individuals with esophageal cancer. For example, if a particular esophageal cancer has a genetic makeup indicating it will be highly sensitive to platinum-based chemoradiotherapy, then this strategy would be recommended prior to an attempt at surgical resection.

Conversely, if the genetic profile within the PI3K/PTEN/AKT/mTOR pathway predicts the cancer would be resistant to standard presurgical treatment, then the patient could be offered an alternative investigational approach or proceed directly to surgical resection.Over time, as additional studies begin to demonstrate similar results, the use of well-defined genetic characteristics as part of a personalized approach to defining the optimal timing of surgical resection might well become the standard in the management of solid tumors.