Uterine (endometrial) cancer is the most prevalent gynecologic tumor in women, with 47,130 new cases and 8,010 deaths in 2012 in the United States. Endometrial cancer is classified into type I and type II disease groups that are very different. Type I tumors, which constitute the majority of cases, are generally diagnosed at an early stage, are endometrioid in histology, and typically have a good prognosis. Type II tumors, although they account for a minority of uterine carcinomas, they are very aggressive. They tend to spread very early in the course of the disease to the entire abdomen. The recurrence rate after surgery and other treatment is very high, in the range of 50-80%, and overall survival for ALL stages is only 30-40% – similar to the poor prognosis of women with ovarian cancer.
This poor prognosis has motivated us to examine the molecular profile of these tumors – in particular, the profile of the genes that participate in repair of DNA breaks. These genes are very important, because when functioning properly they repair all genetic errors that occur in our body every day. If these repair genes are defective, then genetic errors are not being fixed, and cells carrying the errors may multiply and form cancer.
A new class of drug, PARP inhibitors (PARPi), has been discovered to deliver targeted cancer treatment -- they selectively kill cancer cells with defective DNA repair genes and spare healthy cells. These drugs have already shown some benefit in the treatment of ovarian cancer. We therefore propose to determine for the first time, the relative occurrence of DNA repair defects in endometrial cancer.
Our objectives are to (1) determine if a subset of women with endometrial cancer are sensitive to new drugs (PARPi) due to DNA repair gene defects, (2) identify the genetic mutations that are "responsible" for these defects, and (3) determine whether the same patients have inherited mutations in these genes.
Why is this important?
If our proposal is successful, it will have three immediate dramatic clinical applications by enabling us to:
- establish a clinical test to identify women who will benefit clinically from PARPi treatment.
- initiate a pilot clinical study in women with recurrent serous endometrial cancer using the commercially available Olaparib PARPi.
- design a blood test – screening for genetic mutations in DNA repair genes to identify women at risk for endometrial cancer development.
Who will benefit?
Women with serous carcinoma of the uterus may benefit from the results of this study.