Ovarian Endometrioid Carcinoma Research Articles

Spotlight on oncologic outcomes and prognostic factors of pure endometrioid ovarian carcinoma

AimTo determine the prognostic factors related to recurrence and survival, and to evaluate the need for adjuvant chemotherapy in patients with endometrioid type epithelial ovarian cancer (EEOC). MethodsThis study included 63 EEOC patients who were surgically staged. ResultsThe FIGO 2014 stage was stage I in 41 (65 %) patients, stage II in 8 (12.5 %) patients, stage III in 14 (22.5 %) patients. 5-year failure-free survival (FFS) was 78 % in the entire cohort. 15 (23.8 %) patients had disease failure. In univariate analysis, advanced stage (II&III), high grade tumor, presence of ascites, bilateral tumor, presence of omental metastasis, positive peritoneal cytology were prognostic factors for poor FFS. Only the stage was determined to be an independent prognostic factor for disease-failure. According to multivariate analysis, stage II&III was related to a statistically significant hazard ratio for a disease failure of 3.49 (95 % confidence interval: 1.029−11.841; p = 0.045). The effectiveness of adjuvant chemotherapy was assessed for 41 patients with stage I. Eleven (26.8 %) patients with stage I did not receive adjuvant chemotherapy. Whereas 5-year FFS was 88 % in patients receiving adjuvant chemotherapy, that was 91 % in patients without adjuvant chemotherapy (p = 0.923). ConclusionThe independent prognostic factor for recurrence in EEOC was stage only. Adjuvant chemotherapy was not related to improvement in FFS in the early stage EEOC that were completely staged.

Implications for management of ovarian cancer in a transgender man: Impact of androgens and androgen receptor status

A 36-year-old transgender man (assigned female at birth) on exogenous testosterone therapy was found to have stage IIA ovarian endometrioid carcinoma, and underwent adjuvant chemotherapy. Diffuse androgen receptor expression in the tumor initiated a multidisciplinary discussion regarding the safety of continuing exogenous testosterone as gender-affirming hormone therapy.

Histopathology and ARID1A Expression in Endometriosis- Associated Ovarian Carcinoma (EAOC) Carcinogenesis Model with Endometrial Autoimplantation and DMBA Induction.

Background:Ovarian carcinoma is one of the most deadly malignancies in the gynecologic field. The cause is not yet known, and the clinical symptoms are not specific. Endometrioid carcinoma and ovarian clear cell carcinoma can originate from endometriosis and are known as endometriosis-related ovarian carcinoma (EAOC). Development of EAOC experimental animal models is needed for basic research and clinical preparation of human tissue tests. This study aimed to determine the role of the ARID1A gene mutation in the carcinogenetic process of EAOC in experimental animal models induced with DMBA. Methods:In this study, the EAOC experimental model was developed using the autoimplantation technique and DMBA induction. This study involved placebo surgery mice (sham), endometrial autoimplantation, and a combination of endometrial autoimplantation and DMBA induction, which were sacrificed at weeks 5, 10, and 20, respectively. Histopathological assessment and immunohistochemical ARID1A staining with an assessment of positive percentages were carried out on 200 cells. Results:This study produced 1 (20%) atypical endometriosis and 1 (20%) clear cell carcinoma at implantation and after 10 weeks of DMBA induction, and 100% endometrioid carcinoma in the DMBA-induced group. ARID1A staining did not show any significant difference (p = 0.313) in all groups. Conclusion:The combination of endometrial autoimplantation techniques and DMBA induction in the ovary produced atypical endometriosis, clear cell carcinoma, and endometrioid carcinoma, where time is an important factor. There was no significant difference in ARID1A expression between the treatment and control groups.

Updates of Pathogenesis, Diagnostic and Therapeutic Perspectives for Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC) and has a high prevalence in Asia without specific molecular subtype classification. Endometriosis is a recognized precancerous lesion that carries 3-fold increased risk of OCCC. Ovarian endometrioid carcinoma, which also originates from endometriosis, shares several features with OCCC, including platinum resistance and younger age at diagnosis. Patients with OCCC have about a 2.5 to 4 times greater risk of having a venous thromboembolism (VTE) compared with other EOC, and OCCC tends to metastasize through lymphatic vesicular and peritoneal spread as opposed to hematogenous metastasis. There is only mild elevation of the conventional biomarker CA125. Staging surgery or optimal cytoreduction combined with chemotherapy is a common therapeutic strategy for OCCC. However, platinum resistance commonly portends a poor prognosis, so novel treatments are urgently needed. Targeted therapy and immunotherapy are currently being studied, including PARP, EZH2, and ATR inhibitors combined with the synthetic lethality of ARID1A-dificiency, and MAPK/PI3K/HER2, VEGF/bFGF/PDGF, HNF1β, and PD-1/PD-L1 inhibitors. Advanced stage, suboptimal cytoreduction, platinum resistance, lymph node metastasis, and VTE are major prognostic predictors for OCCC. We focus on update pathogenesis, diagnostic methods and therapeutic approaches to provide future directions for clinical diagnosis and treatment of OCCC.

Role of WT1, B-cell lymphoma 2, Ki-67 (Mib1), and Her2/Neu as diagnostic and prognostic immunomarkers in ovarian serous and endometroid carcinoma.

Ovarian cancer is the fifth common cause of death due to cancer in women. It constitutes 3% of all cancers in females and 15%-20% of genital malignancy. Most of the ovarian cancers are serous type followed by the endometrioid type. Sometimes, glands of these two carcinomas are indistinguishable histologically. It also becomes difficult to differentiate these two types when they are poorly differentiated. The aim of this study was to find differences in immunomarker expressions between serous and endometrioid carcinomas and the association of their staining patterns with other clinicopathological prognostic factors. Immunohistochemical staining for WT1, B-cell lymphoma 2 (Bcl2), Ki67 (MIB1), and Her2/Neu were done in paraffin-embedded tissues of histologically diagnosed 38 cases of ovarian serous and endometrioid carcinomas and staining patterns were correlated with other clinicopathological prognostic factors. Of these 38 cases (21 serous and 17 endometrioid), 24 cases were in Stage I/II and 14 cases Stage III/IV. On the other hand, 16 cases were in low grade, 12 cases intermediate grade, and 10 cases high grade. Twenty of 21 serous carcinomas were strongly positive for WT1, whereas most of the endometrioid carcinomas were negative. Ki67 (MIB1) labeling index and Her2/Neu were higher in both higher grade and stages. On the contrary, the intensity of Bcl2 staining was lower in higher grades and stages lesions. The use of WT1 may be useful in resolving diagnostic dilemma between serous and endometrioid carcinoma, especially in difficult cases. Ki67, Bcl2, and Her2/Neu may be used as prognostic markers.

A rare case of endometrioid carcinoma of ovary: A rare case report

A rare case of endometrioid carcinoma of ovary: A rare case report

A phase III, randomized, double blinded trial of platinum based chemotherapy with or without atezolizumab followed by niraparib maintenance with or without atezolizumab in patients with recurrent ovarian, tubal, or peritoneal cancer and platinum treatment free interval of more than 6 months: ENGOT-Ov41/GEICO 69-O/ANITA Trial

BackgroundPlatinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved...

Does complete-staging lymphadenectomy improve survival outcomes in stage I endometrioid epithelial ovarian carcinoma? A multi-institutional retrospective study with propensity score-weighted analysis.

We investigated the prognostic impact of complete-staging lymphadenectomy on patients with clinically apparent Stage I endometrioid epithelial ovarian carcinoma. We conducted a regional multi-institutional retrospective study between 1986 and 2018. Amongst 4897 patients with malignant ovarian tumours diagnosed under central pathological review, 259 women with Stage I endometrioid epithelial ovarian carcinoma were eligible. We evaluated differences in survival of patients with both pelvic and para-aortic lymphadenectomy (Group A) and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation (Group B). To analyse the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. In total, 145 patients (56.0%) received both pelvic and para-aortic lymphadenectomy. With propensity score-based adjustment, estimated survival was better in Group A compared with that in Group B but not significant. Pelvic and para-aortic lymphadenectomy also led to no significant improvement of overall survival in most of the subgroups. However, point estimations of the hazard ratio for lymphadenectomy in patients with an age of 45 or younger (hazard ratio, 0.304; 95% confidence interval, 0.094-0.982), a Grade 1-2 (hazard ratio, 0.441; 95% confidence interval, 0.204-0.954) and T1c2-3 tumour (hazard ratio, 0.449; 95% confidence interval, 0.164-1.231) were better compared with those with the opposite characteristics. Complete-staging lymphadenectomy was not a significant prognostic factor in patients with Stage I endometrioid epithelial ovarian carcinoma, where we still need to explore appropriate candidate for the procedure.

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review.

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

Concurrently Presenting Endometrial And Ovarian Endometrioid Adenocarcinomas- A Clinicopathologic Study Of 52 Cases

Abstract Introduction/Objective Concurrent presentation of endometrioid adenocarcinomas in endometrium and ovary is uncommon, but oft-noted. They may arise from ovarian metastasis of endometrial carcinoma, endometrial metastasis of ovarian carcinoma, or synchronous development of independent primary lesions. Scully and Young criteria have been widely used to differentiate the site of origin.1 Role of a field effect in the genesis of synchronous carcinomas is supported by increasing evidence that endometrioid ovarian carcinomas arise from endometriosis. 2–5 Methods All cases of concurrent endometrioid adenocarcinomas of the endometrium and ovary between 2002 and 2019 in the Mount Sinai health system New York were included, using pathology database (Powerpath) and EMR database (Epic). Results 52 cases of concurrent endometrioid adenocarcinomas of endometrium and ovary were identified between 2002 and 2019. Mean age at presentation was 54.07 years (24–80). 69.2% had synchronous origin, 21.15% had endometrial primary and 3.8% had an ovarian primary. Ovarian endometriosis was identified in 51.9% and complex atypical hyperplasia in 26.9%. Lower uterine segment involvement was seen in 26.9%, bilateral ovarian involvement in 40.3%, fallopian tube involvement in 23% and lymphovascular space invasion in 25%. Different histologic grade of ovarian and endometrial counterparts was noted in 25% cases. Synchronous endometrioid carcinomas had the following characteristics: mean age at presentation 50.6 years, associated with CAH in 33.3% and endometriosis in 66.6%, presentation at stage 1 in 63.8% and lower grade of differentiation (grade 1/2) in 80.5% cases. Conclusion In majority of cases, synchronous endometrioid carcinomas have a younger mean age at presentation, are lower grade tumors, present at stage 1 and have associated endometriosis. It can be inferred that the percentage of synchronous tumors with endometriotic foci would be even higher (with extensive sampling & assuming that the neoplastic process has replaced native benign endometriotic foci) – pointing towards the likely role of endometriosis in the genesis of these tumors.

Recurrent urothelial carcinoma-like FGFR3 genomic alterations in malignant Brenner tumors of the ovary.

Malignant Brenner tumor is a rare primary ovarian carcinoma subtype that may present diagnostic and therapeutic conundrums. Here, we characterize the genomics of 11 malignant Brenner tumors, which represented 0.1% of 14,153 clinically advanced ovarian carcinomas submitted for genomic profiling during the course of clinical care. At the time of molecular profiling, there was no evidence of a primary urothelial carcinoma of the urinary tract in any case. Cases with transitional-like morphologic features in the setting of variant ovarian serous or endometrioid carcinoma morphology were excluded from the final cohort. Malignant Brenner tumors exhibited CDKN2A/2B loss and oncogenic FGFR1/3 genomic alterations in 55% of cases, respectively; including recurrent FGFR3 S249C or FGFR3-TACC3 fusion in 45% of cases. FGFR3-mutated cases had an associated benign or borderline Brenner tumor pre-cursor components, further confirming the diagnosis and the ovarian site of origin. Malignant Brenner tumors were microsatellite stable, had low tumor mutational burden and exhibited no evidence of homologous recombination deficiency. PIK3CA mutations were enriched with FGFR3 alterations, while FGFR3 wild-type cases featured MDM2 amplification or TP53 mutations. The FGFR3 S249C short variant mutation was absent in 14,142 non-Brenner, ovarian carcinomas subtypes. In contrast to malignant Brenner tumors, FGFR1/2/3 alterations were present in ~5% of non-Brenner, ovarian serous, clear cell and endometrioid carcinoma subtypes, most often as FGFR1 amplification in serous carcinoma or FGFR2 short variant alterations in clear cell or endometrioid carcinomas, respectively. Finally, malignant Brenner tumors had overall distinct genomic signatures compared to FGFR-mutated ovarian serous, endometrioid, and clear cell carcinoma subtypes. This study provides insights into the molecular pathogenesis of malignant Brenner tumors, contrasts the extent of FGFR1/2/3 alterations in ovarian serous, clear cell and endometrioid carcinomas and emphasizes the potential value of novel and FDA-approved, anti-FGFR inhibitors, such as erdafitinib and pemigatinib, in refractory, FGFR3-mutated malignant Brenner tumors.

CTNNB1 p.L31P mutation in an ovarian endometrioid carcinoma with synchronous uterine endometrioid carcinoma

We performed next generation sequencing of DNA extracted from the neoplastic tissues obtained from a patient who underwent surgery for a large right ovarian carcinoma (OC) of endometrioid type associated with endometrial cancer (EC). This was done in order to ascertain whether the tumors were synchronous endometrial/ovarian cancers or an advanced metastatic stage from either the ovary or the uterus. Pathologic criteria favoured synchronous EC/OC. We identified a PTEN c.959 T > G (p.L320X) truncating mutation occurring with similar allele frequency in both neoplastic tissues (ovary: 88 %, endometrium 89 %) and a CTNNB1 c.100C > G (p.S37C) activating mutation, with a comparable allelic frequency in both tumor tissues (ovary 51 %, endometrium 52 %). The shared genetic mutations, and the presence of PTEN c.959 T > G (p.L320X) truncating mutation, albeit at low allelic frequency (6 %), in the healthy peritumoral endometrial tissue, appear to confirm the recent literature on a primary endometrial origin for synchronous EC/OC. A third mutation was CTNNB1 c.92 T > C (p.L31 P), a missense mutation occurring with a low allele frequency (3.7 %) only in the ovarian cancer tissue. This mutation is only occasionally described in hepatocellular carcinomas.

Endometrial Cancer Molecular Risk Stratification is Equally Prognostic for Endometrioid Ovarian Carcinoma.

Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a "one-size-fits-all" approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas-inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk POLE mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes (P < 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype-specific management recommendations for patients with ENOC; for example, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials.

Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

Biomarkers of outcome with weekly paclitaxel in platinum-resistant high-grade serous or endometrioid ovarian carcinoma

Objective: The purpose of this study was to evaluate biomarkers of outcome with weekly paclitaxel monotherapy in platinum-resistant epithelial ovarian carcinoma using shallow whole genome sequencing (sWGS).

Magnetic resonance imaging for differentiating ovarian endometrioid carcinoma from clear cell carcinoma

Magnetic resonance imaging for differentiating ovarian endometrioid carcinoma from clear cell carcinoma

Abstract 4872: Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53

Abstract Background: Apoptosis is the therapeutic goal following the administration of anti-cancer drugs. BCL2 and p53 are two important nodes in the apoptosis signaling pathway. Previous reports have shown that the anti-apoptotic protein BCL2 and p53 degrader MDM2 are overexpressed in many solid neoplasms, including ovarian cancers, and associated with poor clinical outcome. Purpose: Since monotherapy in cancer is generally not providing long-lasting clinical responses, here, we hypothesize that concomitant p53 activation (by an inhibitor of MDM2-p53 interaction, e.g. AMG232) and BCL2 inhibition (by venetoclax) induce maximum apoptosis and markedly reduce tumor cell proliferation in ovarian clear cell and endometrioid carcinomas with wild type (WT) TP53. Methods: We tested the anti-proliferative and apoptotic activity of venetoclax (V) alone, AMG 232 alone (A), and a combination of V plus A in ovarian clear cell carcinoma (OVISE cells) and ovarian endometrioid carcinoma cell lines (A2780 &amp; isogenic Cisplatin resistant A2780CisR). Results: 1) A binds the MDM2 protein, blocks MDM2-p53 interaction, and induces p53 expression and activity, 2) p53 effector molecule p21 is robustly induced following the treatment of A, 3) the anti-proliferative activity of V or A was observed by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom, 4) all three cell lines exhibited an increase in annexin V positivity (initiation of apoptotic activity) following V or A treatment, 5) importantly, a combination of V plus A robustly induced the apoptotic markers e.g. cleaved-CASPASE3/7, cleaved PARP1 and BIM protein expression in all cell lines, 6) high mitochondrial depolarization was also observed following the combination of treatment, 7) similar to protein expression data, mRNA data also showed that pro-apoptotic/cell cycle inhibitor transcripts such as p21 and PUMA mRNA expression were significantly increased and 8) normoxic HIF1α degradation is not rescued following the treatment of MDM2-p53 interacting inhibitor A however A-induced p53 activation inhibits hypoxic HIF1α accumulation. Conclusion: These data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy for ovarian clear cell and endometrioid carcinomas patients that retain WT-TP53. Citation Format: Pradip K. De, Jennifer C. Aske, Joseph P. Costello, Ethan Thompson, Nandini Dey. Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4872.

CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53. The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.

Abstract B20: Endometrial cancer molecular risk stratification in endometrioid ovarian cancers: A novel application of precision medicine

Abstract Objective: Endometrioid ovarian carcinoma (ENOC) is associated with a generally more favorable prognosis compared to other ovarian carcinoma histotypes. Nonetheless, patients are still treated with a “one size fits all” approach. While tumor staging offers some stratification, the development of personalized treatment concepts remains elusive. Our group has recently validated the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), to distinguish clinically relevant prognostic groups amongst endometrial carcinomas. ENOC shares risk factors, genomics, and histology with its endometrial counterpart. The aim of our study was to apply and test ProMisE on ENOC. Methods: ProMisE was applied to 509 ENOC after biomarker-assisted review of ENOC histotype. Cases were aligned into low-risk POLE mutant (POLE), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and a final moderate-risk category lacking these biomarkers (p53wt). Kaplan-Meier and multivariate survival analysis were performed. Results: 4% of cases were POLE, 16% MMRd, 71% p53wt, and 10% p53abn. Groups showed distinct progression-free and overall survival (p &amp;lt;0.001), near identical to profiles of endometrial cancers. 5-year PFS was 54% in p53abn, 82% in MMRd, 85% in p53wt, and 100% in POLEmut cases. Median overall survival was reached in p53 mutant cases only. ProMisE classes of ENOC were independent of stage and residual disease in multivariable analysis. Conclusion: ProMisE risk classification provides additional prognostic information in a large cohort of ENOC. Our findings support introduction of ProMisE-stratified treatment strategies to improve patient care across ENOC. Further, ENOC may benefit from parallel efforts under investigation in endometrial carcinoma. Citation Format: Pauline Krämer, Aline Talhouk, Tjalling Bosse, Florian Heitz, Naveena Singh, Felix Kommoss, Sara Brucker, Jessica McAlpine, Stefan Kommoss, Martin Koebel, Michael Anglesio. Endometrial cancer molecular risk stratification in endometrioid ovarian cancers: A novel application of precision medicine [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B20.