Molecular Changes in Circulating Cell-Free DNA from BRCA1 and BRCA2 Mutation Carriers with Tubal Precursor Lesions and Occult Early High-Grade Serous Ovarian Cancer at Risk-Reducing Surgery
Abstract
Ovarian cancer is the fifth leading cause of cancer-related death and is the most lethal cancer of the female reproductive tract in North America. Unfortunately, there are no reliable tests for early detection of the disease, and symptoms that might alert a woman to seek medical treatment at an early disease stage are absent or easily dismissed as being due to minor ailments. If the disease can be detected at an early stage, surgical removal can be curative. The discovery of molecules that can be measured in blood as part of a screening program for ovarian cancer is critically needed. Unfortunately, attempts to identify such molecules have not been sufficiently successful, partially because many studies have largely focused on tissues from patients with advanced disease out of necessity. The most common and lethal type of ovarian cancer, high-grade serous ovarian cancer (HGSC), is an aggressive cancer that resembles cells within the fallopian tube, a structure extending from the ovaries to the uterus. Research indicates that HGSC begins within the fallopian tube, and the tumor cells slough off to start additional tumor growths within the ovary and tissues of the pelvic cavity. Thus, this particular ovarian cancer type is typically diagnosed at an advanced stage and is rarely diagnosed when confined to the fallopian tube or ovary. Women with a mutation in the breast cancer susceptibility genes, BRCA1 or BRCA2, are at a very high risk of developing ovarian cancer. Due to this risk, it is recommended that these women have their ovaries and fallopian tubes removed once childbearing is completed. Upon close examination of the removed fallopian tubes by the pathologist, a small number of these patients are found to have small occult (hidden) cancers or a lesion that is thought to precede and progress to these small cancers. These are the earliest stages of HGSC. Our goal is to develop a blood test to detect such lesions or small cancers still within the fallopian tube. Our center has been collecting research blood samples from all women undergoing removal of their fallopian tubes for reduction of risk for HGSC, and we have identified some of these women, who were subsequently discovered to have precursor lesions or small cancers. In this pilot project grant, we propose to determine whether we can identify chemical modifications to DNA from small early HGSCs or precursor lesions and whether we can detect these changes in DNA circulating in the blood. These findings could form the basis of a blood test that would enable detection of HGSC at its earliest stages when surgery would be most effective. The availability of small early-stage HGSC also affords us the ability to assess whether emerging immune-based treatment approaches to early-stage ovarian cancer might be effective. When detected at an early stage, approximately 10% of HGSC recur. Our findings may support the exploration and use of new immune checkpoint inhibition for the treatment of early-stage HGSC as a targeted approach with less side effects than the currently used conventional toxic chemotherapy. The ability to effectively screen and detect early-stage HGSC and efficiently treat it would greatly impact the survival of this lethal disease, thereby benefiting women in general, as well as those who are part of the Armed Forces Service community.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910226
Entities
People
- Theodore Brown
Organizations
- Mount Sinai Hospital
- United States Army