Abstract:
Epithelial ovarian cancer (EOC) is the 5th cancer-related cause of death among women worldwide. EOC is usually diagnosed at an advanced stage when tumour cells have already spread throughout the pelvis in the peritoneal cavity. Five-year survival rate is around 30% in patients with metastatic diseases but in the fraction of patients whose EOC is diagnosed at an early stage overall survival rate is much higher, approximately 90%. These data suggest that early detection of a greater fraction of EOC could reduce mortality by 15-40%.
Strategies that have been attempted to anticipate the diagnosis of EOC and EC until now have not been successful. The lack of specific and sensitive diagnostic tests for these tumours have given input to translational research to look for new molecular biomarkers that could be used for the early diagnosis. Molecular profiling of tumour biopsies has shown that some types of EOC and EC are characterized by relevant chromosomal abnormalities (i.e. copy number alterations, CNAs), due to high genomic instability, even at an early phase of the tumour development. CNAs could be a biomarker that early intercepts these tumours.
Since most EOC originate from precursor lesions located in the Fallopian tube, the anatomic continuity of tubal lumen, endometrial cavity and cervical canal makes cytological sampling of the cervix hypothetically the best source to capture neoplastic cells. Papanicolaou test (Pap test) is a routine screening procedure for cervical cancer that is already in place in all European countries. We have recently demonstrated that the DNA purified from Pap test smears before high grade serous EOC diagnosis (HGSEOC) contains CNAs compatible with early phase of neoplastic transformation (Paracchini, Mannarino, Romualdi et al. Science Translational Medicine 2023). CNAs were detected through low-pass whole-genome sequencing of DNA derived from Pap test samples (pDNA) in terms of copy number profile abnormality (CPA). CPA values of pDNA from pre-HGSOC women were substantially higher than those in samples from healthy women.
We integrated the CPA score into the EVA (Early oVArian cancer) test to detect HGSEOC presence up to 9 years before diagnosis. The sensitivity of the EVA test was 75% (95% CI,64.97 to85.79), the specificity 96% (95% CI,88.35 to100.00), and the accuracy 81%.
This background of knowledge suggests a new path for the early diagnosis of HGSEOC based on measurement of CNAs or other molecular alterations in the Pap test smears - collected during routine gynaecological screening
Audience Take Away Notes:
- Early diagnosis of HGSEOC is now feasible through analysis of Pap-test smear
- This is a landmark discovery that make realistic the development of a test for early diagnosis
- The workflow described here could be used to implement early diagnosis projects for early disease detection
- This finding provides a practical response to the issue of early diagnosis in EOC
- Future international clinical trials should be designed based on this finding before introducing into a clinical practice
- early diagnosis, reduce death, improve curability of HGSEOC
