1. Fondazione IRCCS Istituto Nazionale dei Tumori - Milano
Incidence
L’innovazione della ricerca traslazionale quale strategia di screening nel tumore ovarico
Delia Mezzanzanica
Fondazione IRCCS Istituto Nazionale dei Tumori - Milano

2. Epithelial Ovarian cancer (EOC) world incidence and mortality
Breast
Colorectum
Lung
Cervix
Stomach
Uterus
Ovary
Thyroid
Liver
Others
Incidence
Breast
Colorectum
Cervix
Lung
Uterus
Stomach
Ovary
Thyroid
Liver
Others
Mortality
death / new cases
About 68% of the women diagnosed with
ovarian cancer will die of their cancer
from Globocan 2012

3. Approaches to reduce mortality
Possible approaches to reduce mortality include:
prevention
screening
better treatment
Effective strategies for screening and early detection of ovarian cancer: still significant unmet needs.
The gold standard should be a randomized trial demonstrating a decrease in ovarian cancer mortality among healthy women who are screened vs. those not screened.

4. Ovarian cancer screening
US PLCO (prostate, lung, colon, ovary) study women randomized for usual care vs. annual CA-125 screening and transvaginal ultrasoud. No significant difference in ovarian cancer mortality after a median follow-up of about 12 years.
UKCTOCS (collaborative trial in ovarian cancer screening) study included more than women;
50% routine care; 25% annual TVUS; 25% annual CA-125 according to the risk of ovarian cancer algorithm (ROCA), which examined change in CA-125 values over time instead of a single CA-125 value.
In the ROCA group: Increase in ROCA TVUS
normal
abnormal finding
Normal controls surgery
Henderson JT; JAMA 2018

5. Ovarian cancer screening
Ovarian cancer mortality did not significantly differ between screened average-risk, asymptomatic women and those with no screening or in usual care. Screening harms included:
psychological distress in women with abnormal test results
surgery (with major surgical complications) in women found to not
have cancer.
This does not apply to women with genetic mutations increasing ovarian cancer risk who are candidates for risk reduction salpingo-oophorectomy.
Henderson JT; JAMA 2018

6. Ovarian cancer screening
There is no strategies for early detection of ovarian cancer that reduces ovarian cancer mortality.
Use of biomarkers:
Samples used for discovery of new biomarkers must be “prediagnostic,” the huge biorepositories from the PLCO and UKCTOCS studies could serve to help with validation of new candidate biomarkers.
Although several markers have been used alone or in combination with CA125, no marker superior to CA 125 has been identified.
TP53 mutations can be detected in blood: possibilities that circulating-tumor DNA could serve as a more specific screening test for high-grade serous cancers.

7. Detection of cancers before they metastasize to distant sites.
Liquid biopsies
Detection of cancers before they metastasize to distant sites.
Diagnostic sensitivity: difficult to assess the presence of mutant template molecules in early-stage
Identification of the underlying tissue of origin. Because the same gene mutations drive multiple tumor types, liquid biopsies based on genomic analysis alone generally cannot identify the anatomical location of the primary tumor.
CancerSEEK blood test: combined PCR–based assays for genetic alterations in 16 commonly mutated genes in a variety of cancer types and protein biomarkers (CA-125; CEA; CA19-9; PRL; HGF; OPN; MPO; TIMP-1) to identifies the presence of relatively early cancers and also to localize the organ of origin of these cancers.
Cohen JD; Science 2018

8. Liquid biopsies
Performance of CancerSEEK, still working when tumor is already present but not yet metastatized
Sensitivity of CancerSEEK by stage
Sensitivity of CancerSEEK by tumor type
Cohen JD; Science 2018

9. TP53 autoantibodies TP53 autoantibodies
The TP53 tumor-suppressor is mutated in virtually all high grade serous ovarian cancers but the predominant epitope(s) recognized by the autologous humoral response is likely expressed on the wild-type TP53 protein
While small volumes of ovarian cancer may not shed sufficient CA125 to be detected, small amounts of tumor-associated antigen(s) could stimulate production of detectable autoantibody.
Definition of a cut-off for TP53 autoantibodies using different case material and normal controls.
Detection of TP53 autoantibody in approximately 20% of ovarian cancers and in 16% that could not be detected with CA125 alone. Elevated titers of TP53 autoantibody 11 months before elevation of CA125 and 23 months before diagnosis in patients not detected with CA125.
TP53 is frequently mutated in a variety of cancers: potential applications for early detection of other types of cancer.
If TP53 autoantibody is used for screening in a general population, more prevalent cancers may also be detected.
Yang WL; CCR 2017

10. TP53 mutation in uterine lavage
Müllerian duct cancers may exfoliate cells development of approaches for lavage of the uterine cavity to detect shed cancer cells.
Patients with ovarian cancer, endometrial cancer, other malignancies, benign lesions involving gynecologic organs.
Lavage as well as corresponding tumor tissue were examined for the presence of somatic mutations (TP53) using next-generation sequencing
TP53 mutations were identified in 80% of
lavage samples of patients with OC.
About 30% of patients with benign lesions
tested positive for mutations mainly in
the KRAS gene.
Possibility to detect even clinically occult OC.
Maritschnegg E, JCO 2015

11. Circulating miRNA for early detection of ovarian cancer
Circulating miRNAs have great potential for the diagnosis or early detection of EOC as alternative to serum proteins
Seven circulating miRNAs (miR-29a-3p; -92a-3p; -200c-3p; -320c; -335–5 p; -450b-5p; -1307–5p) appears to predict ovarian cancer presenting advantages on CA125.
Recognition of more Stage I/II ovarian cancers with significantly fewer false positives.
Ability to discriminate relevant biology more than to quantify tumor burden.
Correct classification of 35/43 (81%) borderline tumors compared to 20/43 (47%; p=0.002) for CA125.
Necessary to demonstrate the model’s potential in the early detection of EOC in a general population or elevated risk setting. Possible use of the huge biorepositories from the PLCO and UKCTOCS studies.
Elias KM; eLIFE 2017

12. Circulating miRNA for early detection of ovarian cancer
Combination of 8 circulating serum miRNAs successfully distinguish ovarian cancer patients from healthy controls and early-stage ovarian cancer from patients with benign tumors.
Yokoi A; Oncotarget 2017

13. Circulating miRNA for early detection of ovarian cancer
The model could also provide information on tumor subtype before initiation of treatment thus guiding treatment strategies.
Yokoi A; Oncotarget 2017

14. Exosomes as liquid biopsies in ovarian cancer
Exosomes contain specific molecules that can provide information about the parent cell as well as the probable target cells protecting information carrying molecules from degradation. Expression levels of specific miRNAs were similar between biopsies and exosomes from the same patient and exosomal miRNA profile varied depending on disease state (benign or cancerous).
Sharma S; Oncotarget 2017

15. Ovarian cancer screening
“To help achieve the goal of reduced mortality from ovarian cancer, I suggest that we tailor therapy to achieve the state of no residual disease, rather than screen to identify cancers in the elusive stage I or II.”
Steven A. Narod,
Women’s College Hospital Research Institute, Toronto,
JAMA 2018