Page 70 - Read Online

Malentacchi et al. J Cancer Metastasis Treat 2020;6:34 I http://dx.doi.org/10.20517/2394-4722.2020.34 Page 3 of 18

Blood circulating biomarkers are currently used in research and have been suggested for tumor
characterization to set a personalized target therapy [e.g., epidermal growth factor receptor (EGFR)
mutation profile in lung carcinoma] in clinical practice. Despite the great development of droplet-based
digital PCR (ddPCR) and the various optimizations of Next Generation Sequencing technologies (NGS),
for both CTCs and ctDNA assays, there is no standardization starting from the pre-analytical phase
[3-5]
through the analytical procedures to platform/technological methods .
Endometrial cancer (EC) is the most frequent gynecological malignant disease affecting the inner lining of
[6]
the uterus . The incidence has increased between 1980 and 2010, due to an increment in average age and
[7]
obesity . Eighty percent of this type of cancer is diagnosed in an early stage [by International Federation
of Gynecology and Obstetrics (FIGO) 2009 classification: stage IA], with five-year survival rates above 80%.
EC is classified into two main histological types: Type I, which is more frequent, and Type II, comprising
[8,9]
several subtypes such as serous and undifferentiated carcinomas . In 2013, the Cancer Genome Atlas
[10]
Research Network (TCGA) suggested implementing classification based on molecular characterization ,
which can be useful to define targeted therapy and monitor cancer development and treatment. Moreover,
there are currently no targeted therapies: in fact, there is no molecular target for treatment, detection, or
monitoring. Finally, 75% of patients have early-stage, low-grade endometrial endometrioid carcinoma
(EEC), which can be treated by surgery; however, about 15% of patients develop recurrence, which cannot
[11]
be correctly predicted at diagnosis .
In this paper, we investigate the classical biomarkers in blood LB and the new ones in other biofluids for
EC [Table 1] by reviewing the data in journal databases.

MATERIALS AND METHODS
The evaluation of papers was performed in PubMed using the following key words: “miRNA”, “circulating
miRNA”, “cell-free DNA/ctDNA”, “lncRNA”, “vesicles/exosomes”, “messenger RNA (mRNA)”, “circular/
circRNA”, and “CTC/circulating Tumor cells” “LB” (blood, urine, saliva, and peritoneal lavage/fluid); AND
“Endometrial cancer/gynecological malignancies”. The search retrieved 130 articles from 2015 to 2020, of
which about 100 were included in this review.

BLOOD-LIQUID BIOPSY
When Liquid biopsy is cited in relation to tumor, the main evaluated biomarkers are CTCs and ctDNA in
[12]
blood. There is no consensus when comparing ctDNA, CTCs, and primary tumor ; the results change
depending on the tumor analyzed and the procedure adopted for biomarkers isolation and characterization.
[13]
For example, these results include 92% for KRAS in colon cancer comparing ctDNA and primary tissue ,
“good correlation” between CTs and ctDNA in colon , and “higher accuracy of ctDNA as prognostic
[14]
[15]
biomarker” in comparison to CTC in overall evaluation in cancer .
Concerning EC, no studies have been reported comparing CTCs, but an interesting study compares the
somatic mutation profile evaluated on ctDNA extracted from plasma to that derived from peritoneal
lavage on 50 patients by NGS, which shows a concordance on KRAS of 42% between primary tissue and
peritoneal lavage ctDNA and 18% for PIK3CA; for plasma ctDNA, this concordance decreases to 7% and
[16]
4%, respectively .

Circulating tumor cells
CTCs were discovered as early as 1869 by Thomas Asworth, who found tumor cells in the blood of a person
who died from metastatic cancer. CTCs were mainly investigated in prostate, breast, lung, and thyroid
carcinomas. Some studies are based on the identification of cells, while other on the characterization of