Ovarian cancer (OC) is the third most diagnosed malignancy and the leading cause of death in female gynecological neoplasms while endometrial cancer (EC) incidence and mortality rates continuing to rise globally. Progress have been performed to identify molecular biomarkers associated to improve the prognosis and to guide the clinical individualized treatment for both cancers. The emerging scientific consensus suggests that all women diagnosed with OC and EC should be tested for the mismatch repair (MMR) deficiency to help guide adjuvant therapy (immunotherapy). There is currently no systematic testing to that end in Norway. The current project aims to fill this clinical gap by a) determining the MMR deficiency by microsatellite instability analysis (MSI) and b) analysing the hypermethylation for BRCA1 and RAD51 gene promoters to identify patients that will get benefit for a) immune checkpoints and b) Poly-ADP Ribose Polymerase (PARP) inhibitors, respectively. Results from this project may be translated into the clinical setting, which jointly underlie the overall Oslo University Hospital (OUH) goal of facilitating evidence-based, and individualized/personalized cancer treatment. The anticipated major impact of this project is clinical and translational, and fully oriented to benefit women with OC and EC in a personalized manner in order to: 1) improve their survival by the selection of an appropriate treatment and clinical management, and 2) improve their quality of life. This approach, the first one in Norway, will promote transdisciplinary collaboration and sharing educational plans of the combined institutional resources. Our project will generate knowledge to provide evidence-based care for the management of their gynecological cancer risk in Norway.
Project description
Ovarian cancer (OC) is the third most diagnosed malignancy and the leading cause of death in female gyneacological oncology. Endometrial cancer (EC) is common, with incidence and mortality rates continuing to rise globally. OC is the most deadly of gynecological malignancies; the majority of women are diagnosed with advanced stage disease when the chance of cure is small.
Endometrial cancer
Whereas early-stage EC is associated with an excellent 5-year relative survival rate (96%), this rate decreases to 18%-20% in patients with distant metastases, and outcomes for these patients are poor (1). Carboplatin plus paclitaxel is the current standard chemotherapy for first-line management of advanced, recurrent and metastatic EC with an objective response rate around 50–60%, a median progression-free survival and an overall survival of 8 months and 15–20 months, respectively (2). Unfortunately, many patients relapse after treatment with this combination. Hormonal treatment is an alternative option in a subset of patients with hormone-receptor positive-tumors, although most patients will require additional systemic treatment. To overcome these challenges, numerous molecular and histological biomarkers have been investigated to determine their ability to function as predictors of recurrence, prognosis and treatment. In 2013, the Cancer Genome Atlas (TCGA) project described four molecular subtypes of EC: polymerase epsilon (POLE) ultra-mutated, microsatellite instability hypermutated (MSI-H)/mismatch repair–deficient subtype (MMRd), copy number low (TP53 wildtype), and copy number high (TP53 abnormal) (3). MMR is a highly conserved mechanism responsible for restoring DNA integrity by correcting single-base mismatches and insertion-deletion loops that may occur during DNA replication. Deficiencies in MMR result in the accumulation of point mutations. It is important to note that EC was recently shown to have the highest prevalence of MMRd/MSI-H tumors across 30 human cancer types. Approximately, 30% of primary and 15% of metastatic or recurrent ECs are MMRd/MSI-H (2). In women with MMRd/ MSI-H metastatic EC progressing after platinum, treatment with PD-1 or PDL-1 inhibitors results in unprecedented response rates between 40 and 60% (2). While the current international guidelines recommend screening for MMR deficiency to all EC patients, in Norway it has not been implemented. Testing for MMRd will inform suitability for immunotherapy and clinical trial enrolment. Ovarian cancer. Newly diagnosed advanced OC is treated with curative intent. However, owing to late diagnosis with advanced-stage disease, most patients have a relapse (after a median of 10 to 18 months), despite being treated with cytoreductive surgery and platinum-based chemotherapy. Patients diagnosed with advanced-stage high-grade serous OC have a 5-year survival rate of 41%, and fewer than 15% survive more than 10 years (4). In 2020, ESMO recommended the predictive biomarker testing for homologous recombination deficiency (HRD) and Poly-ADP Ribose Polymerase (PARP) inhibitor benefit in ovarian cancer (5). Up to 15% of the patients with abnormal results for these biomarkers will be candidates for the PARP inhibitors. Therefore, this recommendation was recently implemented at the Department of Gyneacology at Radium OUH since Q4 2022 to be performed abroad and allowed the combined treatment with anti-VEGF (bevacizumab) and iPARP for maintenance when HRD+ tumors for the patients. However, just like EC, there is no clinical routine for MMRd testing and hypermethylation of BRCA1 and RAD51 promoters. Literature showed that around 10-15% of OC patients are dMMR and hypermethylated of BRCA1 and RAD51 genes (6). In addition, the clinical trials of combination of immunotherapy with other treatment options are ongoing, combined therapies have collaborative effects in contrast to the use of a single treatment. The outcome of the current project may allow to perform these combined therapies available for OC in addition to the recently implemented HRD testing.
The Master project will provide evidence based personalized medicine from the research setting. The Gyneacology Department of the Radium OUH have collected fresh-frozen tumor and blood samples from 300 incident OC and EC cases during the last two years and stored in the prospective biobank for cancer. The current project aims to extract DNA from these samples and perform MSI and methylation analysis for the promoters of BRCA1/2 and RAD51 genes for OC and EC. This will be a prospective observational study having 3-5 years follow-up at the end of study (and which may be continued, if funded further).
References
- (1) Jamieson et al. 2023. https://doi.org/10.1016/j.ygyno.2023.01.025
- (2) Colomba et al. 2023. https://doi.org/10.1016/j.ygyno.2022.11.029
- (3) Vistad I and Bj?orge 2023. https://doi.org/10.1111/aogs.14499
- (4) Garsed et al. 2022. https://doi.org/10.1038/s41588-022-01230-9
- (5) Miller et al. 2020. doi: 10.1016/j.annonc.2020.08.2102.
- (6) Nesic et al. 2020. https://doi.org/10.1158/0008-5472.CAN-21-0774
- (7) Zhu and Lang 2017. https://doi.org/10.3802/jgo.2017.28.e64
- (8) Dominguez-Valentin et al. 2021. https://doi.org/10.1038/s41436-020-01029-1
- (9) Dominguez-Valentin et al. 2020. https://doi.org/10.3390/jcm9072290
- (10) Seppala et al. 2021. https://doi.org/10.1016/j.ejca.2021.02.022