Primary Endometrial Carcinoma Research Articles

Impact of cachexia on disease recurrence and survival outcomes in endometrial cancer patients

ObjectiveCancer cachexia is progressive weight loss due to muscle/adipose tissue wasting and inadequate intake that occurs in response to malignancy. It is an independent predictor of disease recurrence and reduced survival in several cancers. However, cachexia’s relationship with gynecologic malignancy outcomes has only been examined in small studies with limited follow-up and inconsistent definitions of cachexia. This study investigated the impact of cachexia on disease recurrence and overall survival in high-risk endometrial carcinoma patients. MethodsThis retrospective cohort study examined data from patients with high-risk non-metastatic primary endometrial carcinoma treated at a single institution from 2015 to 2020. Treatment for all subjects included total hysterectomy, surgical staging, pelvic external beam radiotherapy with or without adjuvant chemotherapy. Radiation planning CT datasets were used to measure skeletal musculature at the L3 vertebral level. Skeletal muscle index (SMI) was defined as total L3 skeletal muscle cross sectional area (cm2)/height2 (m2), and cachexia was defined based on SMI. Results55 patients were eligible for analysis. Several SMI thresholds were used to define cachexia, and analysis was performed for each definition. Kaplan-Meier and Cox-proportional hazards regression analysis yielded no significant reduction in overall survival (OS) or progression-free survival (PFS) in patients with cachexia, regardless of threshold chosen. However, 4 of 13 definitions of cachexia showed significantly improved OS in patients without cachexia, relative to those with cachexia. There were no significant differences in disease recurrence. ConclusionsCachexia as defined in this study was not associated with poor outcomes in endometrial carcinoma patients based on OS, PFS, or disease recurrence.

Implementation of endometrial cancer molecular subtyping into a hybrid community-academic practice.

We sought to confirm utility of our institution's modified Proactive Molecular Risk Classifier for Endometrial Cancer protocol in our daily practice, which includes mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) immunohistochemistry with in-house next-generation sequencing for POLE, TP53, and CTNNB1. We conducted a retrospective review of all patients in our institution who underwent primary endometrial carcinoma resection from the year prior to protocol implementation (PRE; October 1, 2020, to September 30, 2021) through first year of implementation (POST; October 1, 2021, to September 30, 2022) to compare the distribution of molecular and traditional staging factors using GOG-249 criteria to assign clinical risk. In total, 136 of 260 PRE patients were classified as clinically low risk (LR), of whom 31 were MMR deficient. Of the 157 LR POST patients with endometrioid-type carcinoma, 45 were MMR deficient, 5 were POLE mutant, 5 were TP53 mutant, 56 were of no specific molecular profile (NSMP), and 46 did not receive full protocol testing. Of all 79 POST NSMP endometrioid-type cases, 18 were CTNNB1 mutated and 8 showed L1CAM expression. Our protocol identified 22 (14%) of 157 LR tumors that harbored incipient intermediate- to high-risk molecular aberrations in TP53, CTNNB1, or L1CAM. Moving forward, results of ongoing trials assessing adjuvant therapy decisions based on molecular classification are necessary to confirm protocol utility and identify appropriate modifications.

The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway

Endometrial carcinoma (EC) is a prevalent gynecological tumor in women, and its treatment and prevention are significant global health concerns. The mutations in DNA polymerase ε (POLE) are recognized as key features of EC and may confer survival benefits in endometrial cancer patients undergoing anti-PD-1/PD-L1 therapy. However, the anti-tumor mechanism of POLE mutations remains largely elusive. This study demonstrates that the hot POLE P286R mutation impedes endometrial tumorigenesis by inducing DNA breakage and activating the cGAS-STING signaling pathway. The POLE mutations were found to inhibit the proliferation and stemness of primary human EC cells. Mechanistically, the POLE mutants enhance DNA damage and suppress its repair through the interaction with DNA repair proteins, leading to genomic instability and the upregulation of cytoplasmic DNA. Additionally, the POLE P286R mutant also increases cGAS level, promotes TBK1 phosphorylation, and stimulates inflammatory gene expression and anti-tumor immune response. Furthermore, the POLE P286R mutation inhibits tumor growth and facilitates the infiltration of cytotoxic T cells in human endometrial cancers. These findings uncover a novel mechanism of POLE mutations in antagonizing tumorigenesis and provide a promising direction for effective cancer therapy.

Primary Endometrial Carcinoma with Signet Ring Cells: A Rare and Unusual Entity

Abstract Introduction/Objective The presence of signet ring cells in an endometrial tumor is suggestive of metastasis, as primary tumors with this morphology are extremely rare. As a result, primary tumors are a diagnosis of exclusion, defined by the presence of signet-ring cells usually associated with mucinous endometrioid carcinoma without clinical or radiographic evidence of metastases from breast, stomach, or colon. Methods/Case Report A 64-year-old woman presented with vaginal bleeding. Ultrasound showed a large, heterogenous uterine mass that was diagnosed as poorly differentiated carcinoma on biopsy. Serum CEA was elevated, and CA-125 was normal. Hysterectomy with salpingo-oophorectomy showed a minor endometrial component of grade 3 endometrioid carcinoma and a predominant component of poorly differentiated carcinoma with signet ring cells. The myoinvasive component consisted of the signet ring cells with pools of acellular mucin. Extensive lymphovascular invasion was noted. Cervix, adnexa, and lymph nodes were free of disease. The signet ring cells were positive for CK7, CK20, and CDX2, and negative for ER and Pax-8. The endometrioid component was positive for ER, Pax-8, and CK7, and negative for CK20 and CDX2. E-cadherin staining was lost in the myoinvasive component of the tumor. Loss of MLH1 and PMS2 nuclear expression was seen, and MLH1 promoter methylation was detected in both components of the tumor. Subsequent colonoscopy and imaging did not reveal any other disease sites. Based on histology, pattern of uterine involvement, and lack of extrauterine disease, a diagnosis of primary poorly-differentiated endometrial adenocarcinoma with signet ring cell features was made. The patient was treated with adjuvant chemotherapy and is currently being followed. Results (if a Case Study enter NA) NA Conclusion We present a rare case of primary signet ring carcinoma of the uterus, a challenging diagnosis made after extensive work-up to rule out metastases. Of the previous 9 reported cases, only one was similar to our tumor with distinct endometrioid and signet ring components. Although these primary endometrial tumors are unified by the presence of signet ring cells, there is considerable immunohistochemical heterogeneity. Some reports suggest the signet ring cells have a Mullerian phenotype, while others, including our case, suggest a gastrointestinal phenotype. In presenting this case, we hope to contribute to this entity’s characterization and bring further awareness that the presence of signet ring cells does not exclude a uterine primary.

Dedifferentiated endometrial carcinoma metastasis to axillary lymph node: a case report

BackgroundWe present an unusual case of a left axillary lymph node metastasis from a primary dedifferentiated endometrial carcinoma. This pattern of metastasis is likely the result of circulating tumor cells reaching the node through its arterial blood supply.Case presentationIn this report, a 68-year-old white woman with a dedifferentiated endometrial carcinoma underwent a hysterectomy. She later developed an enlarged axillary lymph node due to metastatic dedifferentiated endometrial carcinoma, treated with chemotherapy and anti-programmed cell death protein 1 immunotherapy resulting in a complete clinical and radiological response.ConclusionA review of the literature reveals the rarity of blood-borne lymph node metastasis, especially with uterine carcinoma. Immunotherapy has shown promising results in the treatment of some subtypes of metastatic uterine carcinoma.

Synchronous Primary Endometroid Ovarian and Endometrial Carcinomas - Pathohistological Criteria for Differential Diagnosis, Clinical Characteristic and Treatment Behavior

Synchronous Primary Endometroid Ovarian and Endometrial Carcinomas - Pathohistological Criteria for Differential Diagnosis, Clinical Characteristic and Treatment Behavior

P16 Block Type Overexpression, p53 Wild Type Reactivity, and Cervical Involvement do not Always Exclude the Diagnosis of Primary Endometrial Squamous Cell Carcinoma (PESCC).

p16 Block Type Overexpression, p53 Wild Type Reactivity, and Cervical Involvement do not Always Exclude the Diagnosis of Primary Endometrial Squamous Cell Carcinoma (PESCC).

Heterogeneity of CD40 Expression in Different Types of High-Risk Endometrial Cancer Affects Discordant Prognostic Outcomes.

The role of immune checkpoint inhibitors in endometrial cancer is limited. At present, the anti-programmed cell death protein 1 (anti-PD-1) antibody is only used in patients with recurrence or metastasis. CD40 is an important immune checkpoint, which is expressed in tumor cells and immune cells, but its distribution characteristics in endometrial carcinoma have not been explored. Sixty-eight cases of primary endometrial carcinoma treated in Peking University People's Hospital from January 2010 to December 2020 were collected, including 28 cases of poorly differentiated endometrioid adenocarcinoma, 23 cases of serous carcinoma and 17 cases of clear cell carcinoma. The relationship of CD40 expression and PD-L1 expression with their prognosis was analyzed by immunohistochemistry. We found that CD40 had higher expression in non-endometrioid endometrial carcinoma, which lead to the worse prognosis. The effect of high expression of CD40 on the prognosis of endometrioid adenocarcinoma was not significantly different, and most patients with good prognosis. We found that the proportion of CD40 distribution in tumor cells and immune cells may be associated with this heterogeneity. The expression of CD40 in different endometrial cancers may indicate the difference prognosis, which may become a potential target for drug treatment of non-endometrioid endometrial carcinoma.

Integration of clinical sequencing and immunohistochemistry for the molecular classification of endometrial carcinoma

PurposeUsing next generation sequencing (NGS), The Cancer Genome Atlas (TCGA) found that endometrial carcinomas (ECs) fall under one of four molecular subtypes, and a POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)-based surrogate has been developed. We sought to retrospectively classify and characterize a large series of unselected ECs that were prospectively subjected to clinical sequencing by utilizing clinical molecular and IHC data. Experimental designAll patients with EC with clinical tumor-normal MSK-IMPACT NGS from 2014 to 2020 (n = 2115) were classified by integrating molecular data (i.e., POLE mutation, TP53 mutation, MSIsensor score) and MMR and p53 IHC results. Survival analysis was performed for primary EC patients with upfront surgery at our institution. ResultsUtilizing our integrated approach, significantly more ECs were molecularly classified (1834/2115, 87%) as compared to the surrogate (1387/2115, 66%, p < 0.001), with an almost perfect agreement for classifiable cases (Kappa 0.962, 95% CI 0.949–0.975). Discrepancies were primarily due to TP53 mutations in p53-IHC-normal ECs. Of the 1834 ECs, most were of copy number (CN)-high molecular subtype (40%), followed by CN-low (32%), MSI-high (23%) and POLE (5%). Histologic and genomic variability was present amongst all molecular subtypes. Molecular classification was prognostic in early- and advanced-stage disease, including early-stage endometrioid EC. ConclusionsThe integration of clinical NGS and IHC data allows for an algorithmic approach to molecularly classifying newly diagnosed EC, while overcoming issues of IHC-based genetic alteration detection. Such integrated approach will be important moving forward given the prognostic and potentially predictive information afforded by this classification.

A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth

Exploring novel molecularly-targeted therapies for endometrial carcinoma is important. The current study explored the potential anti-endometrial carcinoma activity by a first-in-class POLRMT (RNA polymerase mitochondrial) inhibitor IMT1. In patient-derived primary human endometrial carcinoma cells and established lines, treatment with IMT1 potently inhibited cell viability, proliferation, cell-cycle progression and motility, while inducing robust caspase-apoptosis activation. Treatment with the PLORMT inhibitor impaired mitochondrial functions, leading to mtDNA (mitochondrial DNA) transcription inhibition, mitochondrial membrane potential decline, reactive oxygen species formation, oxidative stress and ATP loss in the endometrial carcinoma cells. Similarly, POLRMT depletion, through shRNA-induced silencing or CRISPR/Cas9-caused knockout (KO), inhibited primary endometrial carcinoma cell proliferation and motility, and induced mitochondrial dysfunction and apoptosis. Importantly, IMT1 failed to induce further cytotoxicity in POLRMT-KO endometrial carcinoma cells. Contrarily, ectopic overexpression of POLRMT further augmented proliferation and motility of primary endometrial carcinoma cells. In vivo, oral administration of a single dose of IMT1 substantially inhibited endometrial carcinoma xenograft growth in the nude mice. mtDNA transcription inhibition, oxidative stress, ATP loss and apoptosis were detected in IMT1-treated endometrial carcinoma xenograft tissues. Together, targeting PLORMT by IMT1 inhibited endometrial carcinoma cell growth in vitro and in vivo.

HER2 testing in endometrial serous carcinoma: a comparison of methodologies in an Australian setting

Introduction: Primary endometrial serous carcinoma accounts for less than 10% of endometrial carcinomas but is responsible for 40–80% of deaths.1 HER2 has been shown to be an effective therapeutic target in endometrial serous carcinoma.2,3

Validation and assessment of HER2 FISH probe for endometrial serous carcinoma

Introduction: Primary endometrial serous carcinoma accounts for less than 10% of endometrial carcinomas but is responsible for 40–80% of deaths.1 HER2 has been shown to be an effective therapeutic target in endometrial serous carcinoma.2,3 Buza et al has estimated that there is HER2 overexpression in 25–30% endometrial high grade serous caricnomas, as determined by IHC. She has also proposed a HER2 testing algorithm based on the endometrial serous carcinoma. It is important to note that these studies all use a variety of platforms, reagents, and cut-off scoring systems making it difficult to apply the results in an Australian setting.

Endometrial serous carcinoma with extensive squamous differentiation mimicking primary endometrial squamous cell carcinoma: Clinicopathological and molecular analysis of a case with literature review

In the histological assessment of endometrial carcinoma, the presence of squamous differentiation is generally considered inconsistent with a serous histotype. Herein, we report a case of endometrial serous carcinoma with extensive squamous differentiation mimicking squamous cell carcinoma, with literature review.A 67-years-old-woman underwent hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node resection, omental and peritoneal biopsies, due to a 8cm endometrial mass. Histologically, the tumor showed squamous carcinoma features with positivity for squamous cell markers (p40, p63, cytokeratin-5/6, cytokeratin-34βE12) and negativity for Müllerian markers (PAX8, estrogen receptor, progesterone receptor). No immunohistochemical/molecular alterations typical ofendometrioid carcinoma (i.e., PTEN loss, mismatch repair deficiency, nuclear β-catenin expression,POLEmutation) were observed. P53 showed aberrant pattern and p16 showed basal positivity. The tumor infiltrated the myometrium full-thickness with extensive lymphovascular space invasion. Surprisingly, the sentinel lymph node metastasis showed overt serous carcinoma features. Additional sampling of the endometrial mass revealed a minor. In conclusion, serous carcinoma may show diffuse squamous differentiation. In the case of suspected primary endometrial squamous cell carcinoma, an extensive sampling is warranted.

Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations : A Clinicopathologic Analysis With Re-evaluation of Diagnostic Criteria.

Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (high-risk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20mo; mean, 9mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPV-independent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.

Primary endometrial squamous cell carcinoma with endometrial atypical hyperplasia in elderly women: a case report

Background: Primary endometrial squamous cell carcinoma (PESCC) is a rare entity with poorly understood pathogenesis. Given the difficulty of pathological diagnosis, we report a case of postmenopausal PESCC to highlight the complexity of its immunohistochemical findings.

Association of immunohistochemical profiles with histotypes in endometrial carcinomas

ObjectiveAlthough a large number of endometrial cancer patients are cured with surgery alone, there are significant numbers of patients with more aggressive variants of endometrial carcinoma for whom the prognosis remains poor. We investigated the effects of prevalence, histotypes, and immunohistochemical profiles on prognostic value in a hospital-based population. Materials and methodsA retrospective study of surgically resected primary endometrial carcinoma was included. Immunohistochemical stains were performed on formalin-fixed paraffin-embedded tissue microarray sections for β-Catenin, estrogen receptor (ER), progesterone receptor (PR), HER-2, MLH1, MSH2, MSH6, PMS2, and p53. ResultsLoss of mismatch repair expression was detected in 25.4% of samples (29/114, mean age 57 years) of the tumors. The following loss of expression was observed in patients: MLH1/PMS2 in 16.6% of patients, MSH6 in 7.0% of patients, MLH1 in 0.9% of patients, and MSH6/PMS2/MLH1 in 0.9% of patients. Immunohistochemistry of p53 was analyzed for 111 patients. A total of 13 patients (11.7%, mean age 64 years) had p53-abnormal expression (absent, cytoplasmic or diffuse strong positive patterns), and more than half (9/13, 69.2%) had endometrioid histotype. Abnormalities in p53 were significantly associated with histotype (p = 0.001), advanced tumor stage (p = 0.038), death of disease (p = 0.002), PR percentage (p = 0.002), and HER-2 expression (p = 0.018). Immunohistochemical nuclear localization of β-Catenin was detected in 7.1% of the cohort. The combination of p53 and nuclear β-Catenin expressions was not significantly predictive of disease-free or overall survival. ConclusionThe results of this study are useful for management of endometrial cancer in patients with DNA mismatch repair, abnormal p53 expression, or nuclear localization of β-Catenin.

Molecular classification of endometrial carcinomas: a singleinstitution review (084)

<b>Objectives:</b> To describe endometrial carcinoma (EC) molecular classification utilizing clinical next-generation sequencing (NGS) and immunohistochemistry (IHC) and to assess the clinical, pathologic, and survival outcomes based on molecular data. <b>Methods:</b> We identified all primary and recurrent EC samples of 341-505 cancer-related genes undergoing NGS (MSK-Integrated Mutation Profiling of Actionable Cancer Targets; MSK-IMPACT) from test inception in 2014 through 2020. Samples were classified into the Cancer Genome Atlas (TCGA) molecular subtypes utilizing MSK-IMPACT results for <i>POLE</i> hotspot mutations, <i>TP53</i> mutations, and MSIsensor score; and mismatch repair (MMR) and p53 IHC results collected from pathology reports. Tumors not classified per TCGA based on available NGS and IHC data were excluded from the analysis. Clinical, pathologic, and survival data were obtained for primary ECs undergoing initial staging surgery or treatment at our institution after staging surgery. Only NGS performed prior to documented recurrence was used for survival analysis, to avoid ascertainment bias. Appropriate statistical tests were applied. <b>Results:</b> Clinical MSK-IMPACT sequencing was performed on 2174 ECs. Except for 40 unclassifiable cases, 2134 tumors corresponded to 2066 unique patients, including 1712 (80%) primary and 409 (19%) recurrent tumors. Molecular classification was distributed as 5% <i>POLE</i> (<i>n</i>=113), 22% microsatellite instability-high (MSI-H; <i>n</i>=479), 38% copy-number high (CN-H) (<i>n</i>=818), and 34% CN-low (<i>n</i>=724). MMR-deficiency by IHC was found in 16% of <i>POLE</i>, and IHC-based aberrant p53 expression in 12% of <i>POLE</i> and 2% of MSI-H ECs. Due to the hierarchy of our hybrid classification algorithm, this did not affect molecular designation. Otherwise, all available MMR and p53 IHC results were concordant with NGS results to determine classification. CN-H was 91% non-endometrioid with 67% FIGO G3 within the endometrioid type, while <i>POLE</i>, MSI, and CN-L were 10-32% and 17-21%, respectively (p<0.05). Criteria for survival analysis using primary tumor NGS results were met by 1118 patients. The median follow-up was 22.5 months (0.5-214 months). Three-year progression-free survival was 97% for <i>POLE</i> (SE 2.0), 90% CN-L (SE 2.1), 80% MSI-H (SE 3.1), and 46% CN-H (SE 3.5), (p<0.01). Three-year overall survival was 100% for <i>POLE</i>, 94% MSI-H (SE 2.1), 93% CN-L (SE 2.2), and 71% CN-H (SE 3.6), (p<0.01). CN-H classification remained prognostic for recurrence outcomes when adjusting for age, stage, and histology (HR: 6.2, 95% CI: 1.5-26.6; p=0.04). <b>Conclusions:</b> Our approach to molecular classification involves a hybrid strategy utilizing combined NGS and IHC analysis as a surrogate for whole-exome sequencing employed by TCGA. Our current database is mostly CN-H, which may reflect the referral-based nature of our institution. When applying appropriate criteria for survival analysis, CN-H portends the worst outcomes. Future studies should consider the histological heterogeneity of CN-H when considering treatment options.Fig. 1

Abstract 3879: High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry

Abstract Patients with localized endometrial carcinomas (FIGO IA and IB) have a 5-year relative survival rate of &amp;gt; 90%. Still, some patients with an expected good prognosis experience recurrence of disease which dramatically reduces survival rates. Currently, we lack the knowledge to predict which patients will get recurrence. We used Imaging Mass Cytometry to examine 27 proteins in tissue microarrays of 36 primary FIGO IB endometrial carcinomas, of which 17 later recurred. High dimensional images were segmented to extract single-cell information for each tumor. Distinct epithelial-, stromal- and immune cell types of the tumor microenvironment were identified and phenotyped, using protein expression intensities and unsupervised cell clustering. Neighboring cells of CD8+ cells were extracted and phenotyped. In non-recurrent tumors, more cytotoxic T cells were identified adjacent to two epithelial cell populations characterized by high vimentin and progesterone receptor expression (p &amp;lt; 0.01 and p = 0.02). Tumors that were enriched for vimentin showed significantly better recurrence-free survival than tumors with low vimentin or high alpha-smooth muscle actin (a-SMA) signal (p = 0.026). This study reveals distinct characteristics in the microenvironment of low stage tumors that may aid in identifying high-risk patients. Further, the study provides new insight on the pathogenic processes involved in tumor progression of endometrial cancer. Citation Format: Hilde Eide Lien, Hege Fredriksen Berg, Erling Andre Hoivik, Jone Trovik, Ingfrid Salvesen Haldorsen, Lars Andreas Akslen, Camilla Krakstad. High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3879.

Expression of Growth Hormone-Releasing Hormone and Its Receptor Splice Variants in Primary Human Endometrial Carcinomas: Novel Therapeutic Approaches.

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various tumors, including endometrial carcinomas (EC). However, tumoral receptors that mediate the antiproliferative effects of GHRH antagonists in human ECs have not been fully characterized. In this study, we investigated the expression of mRNA for GHRH and splice variants (SVs) of GHRH receptors (GHRH-R) in 39 human ECs and in 7 normal endometrial tissue samples using RT-PCR. Primers designed for the PCR amplification of mRNA for the full length GHRH-R and SVs were utilized. The PCR products were sequenced, and their specificity was confirmed. Nine ECs cancers (23%) expressed mRNA for SV1, three (7.7%) showed SV2 and eight (20.5%) revealed mRNA for SV4. The presence of SVs for GHRH-Rs could not be detected in any of the normal endometrial tissue specimens. The presence of specific, high affinity GHRH-Rs was also demonstrated in EC specimens using radioligand binding studies. Twenty-four of the investigated thirty-nine tumor samples (61.5%) and three of the seven corresponding normal endometrial tissues (42.9%) expressed mRNA for GHRH ligand. Our findings suggest the possible existence of an autocrine loop in EC based on GHRH and its tumoral SV receptors. The antiproliferative effects of GHRH antagonists on EC are likely to be exerted in part by the local SVs and GHRH system.

Abstract PO-011: The spectrum of pathogenic germline variants in pancreatic cancer patients with multiple primary tumors

Abstract Introduction: Approximately 10% of pancreatic ductal adenocarcinomas (PDAC) are considered hereditary due to pathogenic germline variants in cancer predisposition genes. It is crucial to recognize hereditary PDAC to ensure surveillance of affected individuals and their relatives, and to identify the underlying molecular defects for application of targeted therapies. Methods: The study cohort includes 207 patients with PDAC and additional primary tumors in personal history selected from the Dutch Pathology Archive. Germline DNA was analyzed using two customized targeted next-generation sequencing panels including 26 cancer predisposition genes. Identified variants were checked for pathogenicity. Results: The study includes 207 patients diagnosed with PDAC in combination with two other primary tumors (n = 51), breast (n = 51), colorectal (n = 41), prostate (n = 18), ovarian (n = 8), gastric (n = 5), endometrial (n = 4) carcinomas, and melanoma (n = 29). Germline sequencing identified pathogenic or likely pathogenic variants (PV/LPV) in 43/207 (20.8%) of the patients. Per combination, PV/LPV were detected in PDAC patients with ovarian (4/8), gastric (2/5), melanoma (9/29), breast (12/51), prostate (3/18), colorectal (6/41), and two other primary (7/51) cancers. The most frequently affected genes were ATM (14/43), BRCA2 (7/43; one patient with a concurrent PMS2 LPV), CDKN2A (7/43; 5/7 with Dutch founder p16-Leiden PV), and TP53 (3/43). Eight patients carried PV/LPV in BRCA1 (2/43), MSH6 (2/43), biallelic NTHL1 (2/43), and PALB2 (2/43) genes. Four patients each had a single PV/LPV in BRIP1 (1/43), CDH1 (1/43), CHEK2 (1/43), and RAD51C (1/43). Importantly, more than a half of identified PV/LPV (28/43) occurred in double-strand DNA damage repair genes (14 ATM, 7 BRCA2, 2 BRCA1, 2 PALB2, 1 BRIP1, 1 CHEK2, and 1 RAD51C), potentially conferring a sensitivity to PARP inhibitors and platinum-based chemotherapies. Two patients (2/43) had MSH6 PV, predisposing to Lynch syndrome, potentially responsive to immunotherapies. Overall, almost 70% of PV/LPV carriers and about 14.5% of all cases have potentially targetable germline defects. The median age at PDAC in PV/LPV carriers was only slightly younger (64 years, range: 36 – 82) than in non-carriers (66 years, range: 42 – 84), however, the difference was not significant. Conclusions: Up to 20% of patients with PDAC and multiple primary tumors have a hereditary predisposition to cancer onset; the majority harbor PV/LPV in double-strand DNA damage repair genes. Up to 15% of PDAC patients with multiple primaries and up to 70% of PV/LPV carriers have potentially targetable germline defects. Age-based preselection has limited utility to identify hereditary PDAC, however, the presence of specific other malignancies in personal history strongly indicates on underlying genetic predisposition, and should warrant further investigation and genetic screening. Citation Format: Valentyna Kryklyva, Lodewijk A. A. Brosens, Marjolijn J. L. Ligtenberg, Iris D. Nagtegaal. The spectrum of pathogenic germline variants in pancreatic cancer patients with multiple primary tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-011.