Primary Epithelial Ovarian Carcinoma Research Articles

Combined Interval Cytoreductive Surgery and Carboplatin-Based Hyperthermic Intraperitoneal Chemotherapy in Advanced Primary High-Grade Serous Ovarian Cancer.

Combining interval cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in advanced epithelial ovarian carcinoma (EOC). Although limited, growing evidence regarding carboplatin-based HIPEC highlights its potential. This retrospective study included all patients with advanced primary high-grade serous ovarian cancer who underwent interval CRS combined with carboplatin-based HIPEC at our Canadian tertiary care center between 2014 and 2020. We identified 40 patients with a median age of 61 years. The median peritoneal cancer index was 13 and complete cytoreduction was achieved in 38 patients (95%). Median hospital stay was 13 days and there were four admissions to the intensive care unit (10%) and six readmissions (15%). Severe adverse events occurred in eight patients (20%) and there was no perioperative death. Recurrence was seen in 33 patients (82%) with a median DFS of 18.0 months and a median overall survival of 36.4 months. Multivariate analyses showed that age, peritoneal cancer index, completeness of cytoreduction, occurrence of severe complications, and bowel resection did not significantly impact DFS or OS in our cohort. Interval CRS combined with carboplatin-based HIPEC for advanced primary EOC is associated with acceptable morbidity and oncological outcomes. Larger studies are required to determine the long-term outcomes.

The Cukurova score in the prediction of primary cytoreduction in ovarian cancer

ObjectivePrimary debulking surgery has been the preferred surgical route and is still considered a quality indicator for advanced ovarian cancer surgery. However, a significant number of patients are not amenable...

Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma.

Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated. In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival. Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.

Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma.

To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in epithelial ovarian carcinoma (EOC) treated with primary surgery followed by platinum-based chemotherapy. The records of primary EOC treated between Jan 1st 2002 and Dec 31st 2016 were reviewed according to the including and excluding criteria. CIN was defined as absolute neutrophil count (ANC) after chemotherapy <2.0 × 109/L. Patients with CIN were further divided into mild and severe CIN (ANC <1.0 × 109/L), early-onset and late-onset (>3 cycles) CIN. Clinical characteristic was compared by chi-square test. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier analysis, univariate and multivariate Cox regression models. Among 735 EOC patients enrolled, no significant differences of the prognosis were found between patients with and without CIN, early and late CIN, mild and severe CIN. However, Kaplan-Meier curve (65 vs 42months for CIN vs non-CIN, P = .007) and Cox regression analysis (HR 1.499, 95% CI 1.142-1.966; P = .004) both revealed that CIN was significantly related with better OS in advanced EOC patients, but not for PFS. So, subgroup analysis was further conducted and date suggested that CIN was an independent predictor of better survival in advanced EOC with suboptimal surgery (PFS: 18 vs 14months, P = .013, HR 1.526, 95% CI 1.072-2.171, P = .019; OS: 37 vs 27 months, P = .013, HR 1.455, 95% CI 1.004-2.108; P = .048). CIN might be used as an independent prognostic indicator of advanced EOC, especially for those patients with suboptimal surgery.

Retrospective study of histopathological and prognostic characteristics of primary fallopian tube carcinomas: twenty-year experience (SOCRATE)

ObjectivePrimary fallopian tube carcinoma represents a rare entity, accounting for about 0.75%–1.2% of all gynecological malignancies. The rationale of our study is to describe the prognosis of primary fallopian tube...

Are histomorphologic changes in the fimbrial ends more to blame for primary epithelial ovarian carcinomas than initially thought?

Objective: To investigate the relationship between primary epithelial ovarian tumors and histomorphologic changes in the fimbrial ends (FEs) of the fallopian tubes. Materials and Methods: Twenty-eight serous carcinomas (SCs) and 12 non-serous carcinomas (NSC) were studied. Ovarian and concomitant invasive tumors in FEs were labeled with PAX8, WT-1 and Calretinin. Results: Eighty-six percent of SCs were high grade (HG), 14% of were low grade (LG). 71% of SCs (85% HG, 15% LG) had concomitant invasive tumors in FEs. Serous tubal intraepithelial carcinoma (STIC) was seen in 29% (75% HG, 25% LG), all had concomitant invasive tumors in FEs. The presence of tumors in FEs was statistically significant in SCs (p=0.03). 33% of NSCs had concomitantly invasive tumors in FEs. 67% of endometrioid tumors, 33% of clear cell carcinomas had endometriosis. 50% of mucinous tumors, 67% of endometrioid tumors, 50% of benign Brenner tumors had Walthard nest. Except for mucinous carcinomas, ovarian and concomitant invasive tumors in FEs displayed tubal phenotype (Calretinin-/PAX8+). Conclusion: The results of our study suggest that, invasive tumors and STIC in FEs are not only limited to HGSCs, but can also be seen in LGs. FEs could also be a site of origin for NSCs, however, future studies with more cases are needed.

Abstract 3186: Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation

Abstract Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was conducted to compare the expression of PD-L1 in Middle-Eastern primary epithelial ovarian carcinoma to that in peritoneal metastases and its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastases were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p &amp;lt; 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the heterogeneity of PD-L1 expression in EOC suggests its assessment as a potential biomarker for PD-L1 blockade may require analysis of metastatic lesions. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Felisa De Vera, Yan Kong, Zeeshan Qadri, Saeeda O. Ahmed, Hassan AlDossari, Khawla S. Al-Kuraya. Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3186.

Differentiation between endometriosis-associated ovarian cancers and non- endometriosis-associated ovarian cancers based on magnetic resonance imaging.

Endometriosis-associated ovarian cancer (EAOC) patients show different clinical characteristics compared with non-EAOC patients. However, a few studies are focused on the imaging characteristics of EAOC until now. We assessed MRI characteristics in differentiating EAOC and non-EAOC. We retrospectively analyzed clinical and MRI characteristics from 54 patients with 67 lesions diagnosed with primary epithelial ovarian carcinoma at the Third Affiliated Hospital of Guangzhou Medical University between January 2012 and October 2020. We studied MRI findings such as maximum diameter, morphology, configuration, locularity, features of mural nodules, lymphadenopathy, peritoneal implants, the presence of hyperintensity on T1WI, and hypointensity on T2WI. We also studied the clinical characteristics. Significant MRI variables in univariate analysis were selected for subsequent multivariate regression analysis. This study evaluated the diagnostic performance of the significant MRI variables in univariate analysis. We found that the patients with EAOC, compared with those with non-EAOC, were younger, more unilateral, and had earlier FIGO stage. Univariate analysis revealed that morphology, locularity, growth pattern of mural nodules, and hypointensity on T2WI were factors that significantly differed between EAOC and non-EAOC. In the multivariate logistic regression analysis, locularity and hypointensity on T2WI were independent predictors to distinguish EAOC from non-EAOC. EAOC typically presented as a unilocular mass with hypointensity on T2WI in cystic components. MRI could help distinguish EAOC from non-EAOC. MRI is a promising tool for preoperative diagnosis of EAOC.

Evaluation of Peritoneal Cancer Index as a Prognostic Marker in Primary Advanced Epithelial Ovarian Carcinoma Undergoing “Interval Cytoreductive Surgery” After Neoadjuvant Chemotherapy

Background: Peritoneal cancer index (PCI) has been validated in patients of primary advanced epithelial ovarian carcinoma (PAEOC) undergoing primary cytoreductive surgery (PCS) but not in patients ...

BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor.

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.

A descriptive study of the clinico-pathological and surgical characteristics of patients with primary epithelial ovarian cancer. A cross sectional study

ObjectiveTo study the clinical, pathological and surgical features of primary epithelial ovarian cancer treated at our institution. Methodsfifty-nine patients with primary epithelial ovarian cancer were included. Clinical data collected included patient's age, presenting symptoms, laboratory and tumor markers results as well as preoperative imaging reports. Pathological and surgical findings included were: spread of the disease, histologic type, stage of the disease, type of surgical procedure and amount of residual disease. ResultsMean age of the patients was 54.5 years. Lower abdominal pain was the most common presenting symptom, followed by abdominal distension. The commonest histopathological type was high grade serous carcinoma (72.9%). In our study, majority of patients were diagnosed with stage III disease, accounting for 69.5% of the total number of patients. Complete cytoreduction with no gross residual disease was achieved in 77.3% of patients with stage 3–4 disease. Conclusionclinical and pathological features of primary epithelial ovarian carcinoma in our populations are similar to what is reported worldwide. We have also documented that our surgical approach to the management of ovarian cancer is comparable to the international consensus.

Impact of uterus-preserving surgery on Stage I primary mucinous epithelial ovarian carcinoma: A multi-institutional study with propensity score-weighted analysis.

To investigate the clinical characteristics of women with Stage I primary mucinous epithelial ovarian carcinoma (mEOC) and evaluate the impact of uterus-preserving surgery (UPS) in terms of survival prognosis. A regional multi-institutional retrospective study conducted between January 1986 and March 2017 by reviewing records of the Tokai Ovarian Tumor Study Group. Clinical and pathologic data and survival outcomes were assessed for women with Stage I primary mEOC. The baseline imbalance between women with and those without UPS was adjusted by an inverse probability of treatment weighting method using the propensity score (PS) of independent clinical variables. Among 4730 women with malignant ovarian tumors, 185 had Stage I primary mEOC and were included in the study. The mean age was 47.6years (range 12-87years), and 56 (30.3%) women underwent UPS. After PS-based adjustment, women in the UPS group did not have a poorer prognosis regarding overall survival (P=0.776) or recurrence-free survival (P=0.683). Even after age stratification, there was no statistical difference in survival outcomes between the UPS and non-UPS groups. UPS was not associated with decreased survival and may be a treatment option for women with Stage I primary mEOC irrespective of age.

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a clinical practice guideline.

The purpose of the present review was to provide evidence-based guidance about the provision of cytoreductive surgery (crs) with hyperthermic intraperitoneal chemotherapy (hipec) in the treatment of peritoneal cancers. The guideline was developed by the Program in Evidence-Based Care together with the Surgical Oncology Program at Ontario Health (Cancer Care Ontario) through a systematic review of relevant literature, patient- and caregiver-specific consultation, and internal and external reviews. Recommendation 1a: For patients with newly diagnosed stage iii primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, hipec should be considered for those with at least stable disease after neoadjuvant chemotherapy at the time that interval crs (if complete) or optimal cytoreduction is achieved. Recommendation 1b: There is insufficient evidence to recommend the addition of hipec when primary crs is performed for patients with newly diagnosed advanced primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, outside of a clinical trial. Recommendation 2: There is insufficient evidence to recommend hipec with crs in patients with recurrent ovarian cancer outside the context of a clinical trial. Recommendation 3: There is insufficient evidence to recommend hipec with crs in patients with peritoneal colorectal carcinomatosis outside the context of a clinical trial. Recommendation 4: There is insufficient evidence to recommend hipec with crs for the prevention of peritoneal carcinomatosis in colorectal cancer outside the context of a clinical trial; however, hipec using oxaliplatin is not recommended. Recommendation 5: There is insufficient evidence to recommend hipec with crs for the treatment of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 6: There is insufficient evidence to recommend hipec with crs for the prevention of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 7: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with malignant peritoneal mesothelioma; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol. Recommendation 8: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with disseminated mucinous neoplasm in the appendix; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol.

Immunotherapy of ovarian cancer with a monoclonal antibody specific for the extracellular domain of anti-Müllerian hormone receptor II.

Epithelial ovarian carcinoma (EOC) is the most prevalent and lethal form of ovarian cancer. The low five-year overall survival after EOC diagnosis indicates an urgent need for more effective ways to control this disease. Anti-Müllerian hormone receptor 2 (AMHR2) is an ovarian protein overexpressed in the majority of human EOCs. We have previously found that vaccination against the ovarian-specific extracellular domain of AMHR2 (AMHR2-ED) significantly inhibits growth of murine EOCs through an IgG-mediated mechanism that agonizes receptor signaling of a Bax/caspase-3 dependent proapoptotic cascade. To determine if a single monoclonal antibody (mAb) could inhibit growth of human EOC, we generated a panel of mAbs specific for recombinant human AMHR2-ED and characterized a candidate mAb for humanization and use in clinical trials. We found that our candidate 4D12G1 mAb is an IgG1 that shows high affinity antigen-specific binding to the 7-mer 20KTLGELL26 sequence of AMHR2-ED that facilitates induction of programmed cell death in EOC cells. Most importantly, the 4D12G1 mAb significantly inhibits growth of primary human EOCs in patient-derived xenografts (PDXs) by inducing direct apoptosis of EOC tumors. Our results support the view that a humanized 4D12G1 mAb may be a much needed and effective reagent for passive immunotherapy of human EOC.

Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis.

The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze 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. Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P=0.696) and recurrence-free survival (P=0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

Ultrasound features and clinical outcome of patients with malignant ovarian masses diagnosed during pregnancy: experience of a gynecological oncology ultrasound center

ObjectiveThe number of women diagnosed with ovarian masses during pregnancy has increased in recent years and the management of these women can be controversial. We aim to describe ultrasound characteristics...

Delay in time to adjuvant chemotherapy and its impact on outcome in completely resected advanced ovarian malignancies treated with CRS, CRS+IP and CRS +HIPEC.

e17051 Background: The relationship between initiation time of adjuvant chemotherapy in ovarian cancer and prognosis has remained controversial. This study was done to determine whether time from optimal cytoreductive surgery (CRS) to initiation of adjuvant chemotherapy impacts disease free &amp; overall survival in advanced ovarian carcinoma. Methods: Total of 185 patients with primary advanced epithelial ovarian carcinoma (Stage IIIc or selected Stage IV), underwent optimal cytoreduction (either as upfront or interval) &amp; adjuvant chemotherapy. The analysis of interval between day of surgery and start of adjuvant chemotherapy and its impact on outcome was done. Results: CRS with intraperitoneal (IP) chemotherapy either in the form of IP port or hyperthermic intraperitoneal chemotherapy (HIPEC) was done in 135patients (60+ 75) and CRS alone in 50 patients. The median delay in starting adjuvant chemotherapy was 35 days for the whole cohort (32 days in the CRS group, 34 days in CRS+ IP group and 41 days in CRS+ HIPEC group). Delay in chemotherapy, as defined by more than 42 days had significant impact on DFS in CRS alone group (36 months vs 17 months: p = 0.02) had some impact in patients receiving intraperitoneal chemotherapy (38 versus 28 months; p = 0.78) &amp; no impact on CRS+HIPEC group (35 vs 32 months; p = 0.17). In comparison to HIPEC vs non HIPEC group (CRS &amp; CRS+IP), there was a meaningful impact on DFS with reference to delay in non HIPEC group ( 38 vs 22 months p = .08 whereas in the HIPEC group delay didn’t have any impact(35vs 32 months p = 017). There was trend towards better OS (88 vs 71 months p = 0.49). Conclusions: Delay in starting adjuvant chemotherapy certainly had impact on outcome with respect to CRS &amp; CRS + IP arm (non HIPEC group) whereas the delay didn’t have an impact in the HIPEC group owing to the fact that single dose of chemotherapy during surgery in heated environment may substitute for the delay. However well designed clinical studies needs to be designed to evaluate the impact of single dose of intraperitoneal heated therapy &amp; its interplay in delay on starting adjuvant chemotherapy.

Cardiophrenic lymph node resection in cytoreduction for primary advanced or recurrent epithelial ovarian carcinoma: a cohort study.

To evaluate the clinical outcomes of epithelial ovarian carcinoma patients who underwent cardiophrenic lymph node resection. We retrospectively reviewed the records of all surgically treated patients with advanced epithelial ovarian carcinoma (stages IIIC-IV) who underwent cardiophrenic lymph node resection between 2002 and 2018. Only those in whom cardiophrenic lymph node involvement was the only detectable extra-abdominal disease were included. Patients with suspected cardiophrenic lymph node metastasis on staging images underwent a transdiaphragmatic incision to access the para-cardiac space after complete abdominal cytoreduction achievement. Data on disease-free survival, overall survival, and surgical procedures performed concurrently with cardiophrenic lymph node resection were collected. Of the total 456 patients, 29 underwent cardiophrenic lymph node resection; of these, 24 patients met the inclusion criteria. Twenty-two, one, and one patients had high grade serous epithelial ovarian carcinoma, low grade epithelial ovarian carcinoma, and ovarian carcinosarcoma, respectively. Ten patients had recurrent disease (recurrence group). Fourteen patients underwent cytoreduction during primary treatment (primary debulking group); four underwent cytoreduction after neoadjuvant chemotherapy. Cardiophrenic lymph node resection was performed on the right side in 19 patients, left side in three, and bilaterally in two. The average procedural duration was 28 minutes, with minimal blood loss and no severe complications. Twenty-one patients had cardiophrenic lymph node positivity. The median disease-free intervals were 17 and 12 months in the recurrent and primary debulking surgery groups, respectively. The mediastinum was the first recurrence site in 10 patients. Five patients developed brain metastases. Five patients had an overall survival beyond 50 months. Although rare, the cardiophrenic lymph nodes may be a site of metastasis of ovarian cancer. Although their presence might indicate future recurrence, some patients may achieve long-term survival. Resection should be considered in cases of suspicious involvement to confirm extra-abdominal disease and achieve complete cytoreduction.

Abstract 420: Targeted deep sequencing of mitochondrial DNA in epithelial ovarian carcinomas

Abstract Introduction: Mitochondria are intracellular organelles that play an important role in energy metabolism, reactive oxygen species generation, and apoptosis. They possess their own haploid genome distinct from nuclear DNA, and mutations in mitochondrial DNA (mtDNA) have previously been linked to cancer risk, disease progression, and treatment response for multiple tumor types. However, the spectrum of mtDNA variation in epithelial ovarian carcinoma (EOC) and associations with clinical characteristics have not been fully explored. Methods: We extracted mtDNA from fresh frozen EOC tumors of women diagnosed with primary invasive epithelial ovarian, fallopian tube, or peritoneal carcinoma, and performed targeted sequencing using the Illumina MiSeq Reporter mtDNA workflow. Homoplasmic and heteroplasmic SNVs and indels were called using an in-house bioinformatics pipeline. We estimated mtDNA haplogroup using Haplogrep and compared to results from available germline mtDNA SNP genotyping. We derived regional weighted variant burden scores based on mtDNA functional domains, accounting for underlying haplogroup, heteroplasmic fraction, and predicted functional impact. To assess potential differences in variant burden by histotype, we compared burden scores using Kruskal-Wallis testing. Among high-grade serous tubo-ovarian cases, we explored associations with overall survival (OS) using Cox proportional hazards regression. After quality control filtering, 389 mitochondrial genomes were analyzed, including those from 320 tubo-ovarian high-grade serous tumors, 42 endometrioid tumors, and 18 clear cell tumors. Results: Accounting for predicted haplogroup, we identified a median count of two global private heteroplasmies per tumor (range: 0-9). Elevated mutation rates were identified in the regulatory control region as well as among the various mt-tRNAs (&amp;gt;3 per 10kb per sample) relative to the remainder of the mtDNA. The majority of recurrent variants across tumors were also identified in the mtDNA control region. We did not observe an association with overall mtDNA variant burden and patient age at diagnosis. Regional mtDNA burden scores revealed a significant association with histotype (P&amp;lt;0.001) for the oxidative phosphorylation complex IV genes, with higher burden in tubo-ovarian high-grade serous and clear-cell tumors relative to endometrioid tumors. For patients with tubo-ovarian high-grade serous tumors, increased variant burden in MT-CO1 (cytochrome C oxidase I) was associated with improved OS (HR = 0.32; 95% CI = [0.14,0.70], LRT P = 0.001) after adjustment for age, stage, and debulking status. Conclusions: We demonstrate a wide range of tumor mtDNA variant patterns in the largest known collection of EOC patients. This work provides the first extensive evaluation of mtDNA variation in these diseases and highlights the potential prognostic relevance of mitochondrial dysfunction. Citation Format: Nicholas B. Larson, Stacey J. Winham, Chen Wang, Jared M. Evans, Sebastian M. Armasu, Bryan M. McCauley, Sean J. Yoder, Lan Min Zhang, Catherine M. Phelan, Ellen L. Goode. Targeted deep sequencing of mitochondrial DNA in epithelial ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 420.

Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma.

Anterior gradient 2 protein belongs to a family of chaperone‐like proteins, namely protein disulfide isomerase. Generally, AGR2 is highly expressed in mucus‐secreting cells and endocrine organs, and in this study, we aimed to evaluate AGR2 and cell cycle molecules in epithelial ovarian cancer and its implications on prognosis. One hundred seventy‐five patient's samples that were diagnosed with primary epithelial ovarian carcinoma were selected. All the patients were treated with platinum‐taxane standard chemotherapy after surgery and CA125 serum levels were routinely determined. Four‐micrometer‐thick sections were processed by immunohistochemistry using an automated immunostainer, Ventana BenchMark AutoStainer with AGR2, cyclin D1, p21WAF1, and p53. Forty‐nine of 167 cases (29.3%) showed strong to moderate cytoplasmic marking of AGR2, and 118 (70.7%) had weak to negative expression. The absence of the AGR2 protein was observed in high‐grade serous carcinoma (P < .001) and significantly associated with disease‐free survival (DFS; P = .034). The expression of G1‐S phase‐regulatory proteins showed loss of p21 in high‐grade serous carcinoma (P < .001) and was related with poor DFS (P = .003). Strong and diffuse immunoexpression of p53 plus complete absence of p53 staining was interpreted as likely indicating a TP53 gene mutation. This result showed worse DFS alone (P = .012) and combined with low levels of AGR2 (P = .005). The expression profile of AGR2 and cell cycle proteins here presented was showed as good prognosis marker in epithelial ovarian cancer. This finding suggests AGR2 and as putative biomarker of disease progression in chemotherapy‐treated high‐grade serous carcinoma patients.