Liquid Biopsy-based Detection of Early Stage Gynecological Cancers

According to the American Cancer Society, in there were an estimated 110,070 new cases diagnosed and approximately 32,120 deaths from gynecologic cancers in the U.S. in 2018. Of the five most common types of gynecologic cancer (cervical, ovarian, uterine, vaginal, and vulvar), ovarian cancer is associated with the highest mortality rate and is the fifth leading cause of cancer death. With the exception of pap smear for cervical cancer, there is no specific screening test for any gynecologic cancer. If detected early, mortality rate of ovarian cancer can be reduced by as much as 90% and this presents a huge unmet need. Among many potential biomarkers, circulating tumor DNA (ctDNA) has emerged in the last few years as a major tool for precision medicine in oncology. ctDNA exhibits genetic and epigenetic alterations from its cell of origin and is therefore becoming a key biomarker in non-invasive early detection using liquid biopsy. In this talk, I will highlight several challenges that still exist, despite rapid progress, in widespread clinical usage of ctDNA for cancer screening, notably for the early detection. These include limited sensitivity of current technology to detect small tumors with very low levels of mutant ctDNA present, a priori unknown somatic mutations and inability to distinguish ctDNA from cfDNA from normal cells released by non-malignant cells during normal cellular turnover. I will also review some of the techniques that are being used to overcome these challenges such as ultra-deep next-generation sequencing, customized bioinformatics tools and, machine learning to build classification models by integrating multiple analytes (such as proteins, transcriptome, miRNA and exosomes). I will conclude by providing a brief commentary on the future prospects of this promising technology.

Learing Objectives:

1.    What is the current level of detection (LOD) for mutant allele fraction that most liquid-biopsy technologies/test can offer? A: 0.5%

2.    What is the challenge of using a larger sequencing panel for the detection of ctDNA? A: requires a greater input of DNA and higher sequencing costs due to lower throughput of sample