Detecting pre-cancers by liquid biopsy: The proof-of-principle and dilemma

In contrast to the previously successful TCGA goals of cataloguing the genomic landscape of advanced disease, we currently lack understanding of the multi-omics landscape and ordering of the sequence of genetic events and... [ view full abstract ]

In contrast to the previously successful TCGA goals of cataloguing the genomic landscape of advanced disease, we currently lack understanding of the multi-omics landscape and ordering of the sequence of genetic events and immunologic features which lead to cancer. This limited understanding of pre-cancer biology ultimately becomes an insurmountable roadblock for early cancer detection and prevention: as cancer-driver mutations are now being reported with increasing frequency in aging but apparently normal tissues, we cannot distinguish between a benign molecular lesion conferring a proliferative growth advantage and a clonal population committed to malignancy.  This results in a clinically-relevant dilemma wherein the technology to detect mutations is available but the pre-cancer knowledge gap means mutation detection is not actionable.

Endometrial cancer is the most common gynecologic malignancy in industrialized countries and, given the rise in obesity, both its incidence and associated mortality are increasing. There is no screening test for this cancer. Recently, NGS technologies have been coupled to an almost abandoned technique first introduced sixty years ago, the uterine lavage, to detect endometrial and ovarian cancers. We demonstrated the ability to sequence DNA isolated from uterine lavage fluid to detect even microscopic cancers.    

We now report the clinical and molecular follow-up of an originally asymptomatic 67yo female with histology-proven benign endometrium with no evidence of hyperplasia or cancer but with lavage-detected, oncogenic PTEN driver mutations who returns one year later with postmenopausal bleeding and a single microscopic focus of endometrial cancer.  The same PTEN mutations detected in lavage were also present in her tumor.  We calculated that the shared mutations across samples were not likely to occur by chance alone (p < 3x10^-7).

Using an integrated liquid biopsy-based and cancer-targeted sampling approach, we have established a benchmark for earliest endometrial cancer detection.  This illustrative case provides the first demonstration that future, tumor-specific mutations can be identified in an asymptomatic individual without clinical or pathologic evidence of cancer.  The results are discussed in the context of follow-up of other patients and molecular profiles, the implications for precision medicine and the urgent need for understanding pre-cancer biology.