Personalized therapy in endometrial cancer: challenges and opportunities

Abstract

Early stage endometrial cancer is generally curable. However, progress in the treatment of advanced and recurrent endometrial cancer has been limited. This has led to a shift from the use of traditional chemotherapeutic agents and radiotherapy regimens to the promising area of targeted therapy, given the large number of druggable molecular alterations found in endometrial cancer. To maximize the effects of directed targeted therapy, careful molecular characterization of the endometrial tumor is necessary. This represents an important difference in the use of targeted therapy vs. traditional chemotherapy or radiation treatment. This review will discuss relevant pathways to target in endometrial cancer as well as the challenges that arise during development of a personalized oncology approach.

Figure 1

Druggable signaling pathways in endometrial cancer. Abbreviations: EGF, epidermal growth factor; IGF, insulin-like growth factor; TGFα, transforming growth factor α; FGF, fibroblast growth factor; HER, human epidermal growth factor receptor; EGFR, epidermal growth factor receptor; IGFR1, insulin-like growth factor receptor 1; FGFR2, fibroblast growth factor receptor 2; ATP, adenosine triphosphate; AMP, adenosine monophosphate; VEGF, vascular endothelial growth factor, PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; GRB2, growth factor receptor-bound protein 2; RAS, rat sarcoma gene; Raf, V-raf-1 murine leukemia viral oncogene homolog 1; MEK, mitogen activated protein kinase kinase; ERK, mitogen activate protein kinase; SRC, V-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3 Kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; AKT, v-akt murine thymoma viral oncogene homolog 1; PKA, protein kinase A; LKB1, liver kinase B1; AMPK, adenosine monophosphate kinase; mTORc, mammalian target of rapamycin Complex.

Figure 2

Comparison between tissue obtained from a primary hysterectomy specimen and tissue obtained from core needle biopsy at the time of recurrence. Recurrence tissues are much smaller, have less tumor cells, and commonly consist of tumor cells admixed with stroma. This latter feature may necessitate the use of laser capture microdissection prior to PCR-based molecular diagnostics testing.