Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer

PurposeWe sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models.Results1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of MLH1. Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%, p=<0.001) and with the presence of LN metastasis (20.3 vs 10.5%, p=0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99 p=0.013; PORTEC p=0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70; p=0.003) but not overall survival.ConclusionWhile MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and MLH1 hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol

To report clinical and pathologic relationships with disease spread in endometrial cancer patients

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC

Imaging across the Life Span: Innovations in Imaging and Therapy for Gynecologic Cancer

This review addresses the optimization of multidisciplinary care of patients with gynecologic cancer to include imaging as a central component of radiation treatment planning and delivery

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Peer reviewe

Management of a rapidly enlarging new adnexal mass: a rare case of desmoplastic small round cell tumor of the ovary arising in pregnancy

Background: Desmoplastic small round cell tumor (DSRCT) is an extremely rare sarcomatous tumor, which is most commonly seen in men. Clinicians managing a patient with a rapidly enlarging mass in pregnancy should be aware of the risk for malignancy. Case: A 31-year-old woman was found to have a newly enlarged ovarian mass in the second trimester. She subsequently underwent a laparotomy for removal, with chemotherapy for presumed poorly differentiated ovarian malignancy. Ultimately she was diagnosed with a desmoplastic small round cell tumor of the ovary and had progression at time of delivery. Following cesarean delivery, she had a tumor reductive surgery. She has completed 12 cycles of intensive chemotherapy and is alive with disease at 14 months. Conclusion: Care should be taken not to delay evaluation of a rapidly enlarging mass in pregnancy. While this tumor type is extremely rare, a malignancy in pregnancy must be ruled out in this clinical scenario

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series

Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma (OCCC) are limited. This case series sought to report tumor characteristics and oncologic outcomes in a small group of patients treated with combination lenvatinib and pembrolizumab.A retrospective analysis of patients with ovarian clear cell carcinoma treated with combination lenvatinib and pembrolizumab at a single institution was performed. Patient and tumor characteristics were collected including demographics and germline/somatic testing. Clinical outcomes were also evaluated and reported.Three patients with recurrent OCCC were included in the study. The median age of patients was 48 years old. All patients had platinum-resistant disease and had received 1–3 prior lines of therapy. The overall response rate was 100% (3/3). Progression-free survival ranged from 10 months to not-yet-reached. One patient remains on treatment, while the other two died of disease with overall survival of 14 and 27 months.Combination lenvatinib-pembrolizumab demonstrated favorable clinical response in these patients with platinum-resistant, recurrent, ovarian clear cell carcinoma

A Novel Estrogen Receptor β Agonist Diminishes Ovarian Cancer Stem Cells via Suppressing the Epithelial-to-Mesenchymal Transition

Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer

Recurrence rate in early-stage epithelial ovarian cancer: Is there a role for upfront maintenance with PARP inhibitors in stages I and II?

Objective: To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status. Methods: Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed. Results: 89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001). Conclusions: Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases