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One hundred fifty yolk sac tumors (YSTs) of the ovary in patients from 1 to 61 (mean: 21.5) years of age are described; 75% of the patients were in the second and third decades and only 1 was above 50 years of age. The clinical manifestations were typically related to a fast-growing adnexal mass; endocrine manifestations (hirsutism) were present in only 2 cases. The tumors were all unilateral and 70% were ≥15 cm; an associated dermoid cyst was present in 20 cases. The tumors were solid and cystic in 57% of the cases, 25% were multicystic, and 18% uniformly solid. The solid tissue was typically tan to pink or yellow and often friable with hemorrhage and necrosis; smaller solid neoplasms were sometime uniformly yellow. The most common histologic pattern was reticular composed of an irregular meshwork of spaces that was conspicuous in 68% of the neoplasms but present to at least a minor degree in all of them. That appearance almost always merged with small to large cysts that were prominent in about 40% of tumors. In 25% of the tumors, cysts sometimes associated with a cellular stroma (the polyvesicular pattern), were present but conspicuous in only half these cases. One third of the tumors had a labyrinthine pattern, 22% glands, and 6% a festoon pattern. Papillae with a central blood vessel (Schiller-Duval bodies) were seen in one-third of the tumors but were numerous in only 5% of them. Nonspecific appearing papillae were seen in 10% of the tumors. A solid growth of cells with pale cytoplasm was seen in one-third of the tumors but was conspicuous in only half of that subset. The solid appearance was typically reminiscent of that of dysgerminoma, but lacked the septa and lymphocytic infiltrate of that neoplasm. Nine tumors had a component of cells with scant cytoplasm resulting in a blastema-like appearance and 3 had cells with abundant clear cytoplasm. Cords and clusters of cells were common but did not dominate the microscopic appearance. The stroma typically had a nonspecific collagenous to edematous appearance. Stromal luteinization was seen in 12 tumors; in 5 this was likely due to the patient being pregnant. Two tumors had minor foci of cells that resembled hepatocytes. Hyaline bodies were seen in most of the tumors and were often conspicuous. The neoplastic cells typically had modest amounts of lightly staining cytoplasm and only mild nuclear pleomorphism. Cells lining cysts were often flattened sometimes resulting in a deceptively innocuous appearance. Many of the tumors (mostly consultation cases), caused diagnostic difficulty; tumors in the differential diagnosis included clear cell carcinoma, embryonal carcinoma, Sertoli-Leydig cell tumor, and juvenile granulosa cell tumor. The patient age and marked elevation of the serum alpha-fetoprotein level (if measured) is helpful in many of these considerations. The overtly malignant gross appearance of most YSTs contrasts with certain other tumors in the differential and the association of some YSTs with dermoid cyst and many clear cell carcinomas with endometriosis may be helpful. The vast majority of ovarian YSTs are dominated microscopically by merging of reticular and cystic patterns which, although focally mimicked by other neoplasms, are in general characteristic, and distinctive features of other neoplasms are absent. Immunohistochemistry, particularly for alpha-fetoprotein and glypican 3, and lack of staining for various markers of other neoplasms is helpful but overlap exists and these results must be considered in the context of the overall clinical, gross, and microscopic features. YSTs dominated by hepatoid and glandular features are rare and their categorization as YSTs should be done cautiously if thoroughly sampled tumors show no evidence of classic features of YST emphasized herein and first elaborated by the Danish investigator Gunnar Teilum whose seminal observations have stood the test of time.

BACKGROUND: In breast cancer patients fulfilling the Z0011 trial criteria, axillary lymph node dissection (ALND) is reserved for patients with a high nodal burden of ≥3 metastatic nodes. In this group of patients, to avoid an ALND, neoadjuvant chemotherapy (NACT) could be given instead to achieve nodal pathological complete response (pCR). However, the benefit of NACT in achieving nodal pCR and avoiding ALND in this group of patients is unknown. We aimed to determine the nodal pCR rate in this group of patients who otherwise would have needed an ALND. METHODS: cT1-2N0 breast cancer patients, with histologically proven nodal metastasis, who underwent NACT were identified from a prospectively maintained database. The sonographic criteria of ≥3 abnormal nodes, which has been reported as highly predictive of high nodal burden, was then used to identify the high nodal burden group. Nodal pCR was determined based on the ALND following NACT. RESULTS: Twenty-four patients with high nodal burden were identified. Mean age was 55.2 years. 91.7% had invasive ductal carcinoma and 29.2% had grade III cancer. 54.2% achieved nodal pCR which was associated with ypT (P=0.006). Nodal pCR was 75%, 70% and 30% in the triple negative, human epidermal growth factor receptor2 (HER2) positive and ER/PR+HER2- tumors, respectively. CONCLUSIONS: In the postulated T1-2 breast cancer patients with high nodal burden, needing an upfront ALND, NACT could result in nodal pCR of 54.2%, with higher pCR in certain subtypes. Hence, to minimize ALND risk, NACT should be offered in this high nodal burden group.

BACKGROUND Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients. LAY SUMMARY Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

Background Multiloculated pelvic cysts are commonly misdiagnosed as ovarian tumors or malignancies. We report 2 patients diagnosed with subserosal adenomyotic cysts and peritoneal inclusion cysts, mimicking multiloculated pelvic tumors. We discuss their clinical presentation, investigations, operation findings, and histopathology, present a literature review. Cases Case 1 was a 44-year-old patient with abnormal uterine bleeding. Imaging showed an enlarging multiloculated cystic structure over the right uterine wall. She underwent a diagnostic laparoscopy and right salpingo-ophorectomy. Intra-operatively, she was found to have multiple subserosal uterine cysts, diagnosed as adenomyotic cysts on histology. Case 2 was a 50-year-old patient with history of laparoscopic cystectomy done 20 years ago. She was incidentally found to have a multiloculated cystic lesion in the pelvis. The lesion was located midline, anterior and superior to the uterus and bladder. She underwent a total abdominal hysterectomy, bilateral salpingo-ophorectomy, and bladder peritonectomy. Intra-operatively, multiple cystic lesions were noted over the anterior and fundus of uterus, bladder peritoneum, and pelvic side walls. The condition was confirmed to be peritoneal inclusion cysts on histology. Conclusion Subserosal adenomyotic cysts are a rare presentation of adenomyosis. They typically occur in premenopausal women. Treatment is usually by hormonal medications or surgical excision. Many patients with peritoneal inclusion cysts have a history of peritoneal insults. Surgical excision is the most commonly described management as they often mimic malignancy. Both conditions are unusual presentations of multiloculated pelvic masses. A high recurrence rate is found, hence long-term follow-up with imaging is essential., Highlights • Adenomyotic cysts can present as multiple cystic lesions found within the uterine myometrium, submucosal or subserosal layers, lined with endometrial epithelium and stroma. • Patients with adenomyotic cysts commonly present with dysmenorrhoea or dysfunctional uterine bleeding. These cysts are usually excised surgically or treated with hormonal methods. • Peritoneal inclusions cysts are benign aggregate masses of variable sized, fluid-filled, mesothelial lined cysts of the pelvis and abdomen, commonly with a history of previous insult to the peritoneum • Surgical excision of the peritoneal inclusion cysts is the most common treatment option, often for histological diagnosis as it mimics malignancy. • Recurrence is common for both conditions, hence long term follow ups with imaging should be considered.

Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases. National Medical Research Council (NMRC) National Research Foundation (NRF) J.N is funded by the National Research Council Singapore Clinician-Scientist Award (NMRC/CSAINV/0017/2017). Additional funding was provided by the National Research Foundation Singapore under its NMRC Centre Grant Programme (NMRC-CG-RIE 2020 - Project No. NMRC/CG/M003/2017). AstraZeneca provided funding for ovarian cancer research.

(1) Background: Smartphone dietary assessment apps can be acceptable and valid data collection methods but have predominantly been validated in highly educated women, and none specifically measured eating-out habits in young adults. (2) Methods: Participants recorded their food and beverage consumption for three days using the Eat and Track (EaT) app, and intakes were compared with three dietitian-administered 24-h recall interviews matched to the same days as the reference method. Wilcoxon signed-rank or t-tests, correlation coefficients and Bland&ndash, Altman plots assessed agreement between the two methods for energy and percentage energy from nutrients (%E). (3) Results: One hundred and eighty nine of 216 participants (54% females, 60% resided in higher socioeconomic areas, 49% university-educated) completed the study. There were significant differences in median energy intake between methods (p &lt, 0.001), but the EaT app had acceptable agreement for most nutrient densities at the group level. Correlation coefficients ranged from r = 0.56 (%E fat) to 0.82 (%E sugars), and between 85% and 94% of participants were cross-classified into the same or adjacent quartiles. Bland&ndash, Altman plots showed wide limits of agreement but no obvious biases for nutrient densities except carbohydrate in males. (4) Conclusions: The EaT app can be used to assess group nutrient densities in a general population of 18-to-30-year olds.

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cordstromal tumors including adult granulosa cell tumors (AGCTs). We performed whole genome sequencing on ten AGCTs with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that AGCT with mutated TERT promoter have increased expression of TERT mRNA compared to those with wild-type TERT promoter. AGCT with TERT C228T mutation exhibited significantly longer telomeres compared to AGCT with TERT wild-type promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary AGCTs (22%), 24 of 58 recurrent AGCTs (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log rank test). In seven AGCTs, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggests that TERT C228T mutations may have an important role in progression of AGCT. Telomeres are conserved, repetitive (TTAGGG) DNA-protein complexes that are added to the ends of chromosomes by the enzyme telomerase to prevent DNA damage and maintain replicative potential. Telomere attrition during DNA replication induces genomic instability that can result in tumorigenesis. Telomerase consists of a catalytic protein subunit known as telomerase reverse transcriptase (TERT) and a functional RNA called telomerase RNA component (TERC). TERT is highly expressed in stem cells and is silenced upon differentiation in somatic cells. Most cancer cells attain proliferative immortality by upregulating the TERT gene to maintain telomere length and telomerase activity. The known mechanisms of telomerase activation include mutations in the TERT promoter, TERT gene amplification, CpG methylation at the TERT promoter, changes in alternative splicing of TERT pre-mRNA and upregulation of transcriptional activators. Approximately 90% of cancers express TERT, while the remaining 10-15% of cancers maintain their telomere length through a telomerase-independent method called alternative lengthening of telomeres. TERT promoter mutations were first reported in familial melanoma and subsequently in sporadic melanoma. There are two hot-spot TERT promoter mutations, C228T and C250T, each generates an identical 11 base pair sequence containing a consensus binding motif for ETS transcription factors, and functions as either a transcriptional activator or repressor to regulate telomerase expression. These two mutations are implicated in the activation of telomerase in other malignances such as central nervous system tumors, hepatocellular carcinomas, bladder cancers and thyroid cancers. A recent study on TERT promoter mutations in gynecological malignancies, including ovarian and uterine carcinomas, reported TERT hot-spot mutations in 15.9% of ovarian clear cell carcinomas. However, it is unknown whether TERT promoter mutations are frequent in sex cord-stromal tumors, including adult granulosa cell tumors (AGCTs). In this study, we evaluated the biological and clinical significance of TERT promoter mutations, specifically C228T, in total of 251 primary ovarian sex cord-stromal tumors.

BACKGROUND: Adult granulosa cell tumors (AGCT) represent 3-5% of all ovarian cancers. These tumors are characterized by their slow growth and usually occur in postmenopausal women with a median age of diagnosis of 50 to 54 years. The majority of patients are diagnosed as stage I and are treated with surgery to remove their ovaries and uterus. Although these treatments are effective at first, one third of patients relapse leading to mortality in 50-80% of relapsed patients. The best course of treatment for patients with recurrent advanced stage disease is optimal debulking surgery. Currently, there are no effective treatments available for patients where surgery is not an option. Our research team previously discovered a somatic missense mutation (c.402C>G; pC134W) in the transcription factor Forkhead box L2 (FOXL2) in 97% of AGCTs. We also discovered frequent activating telomerase reverse transcriptase (TERT) promoter mutations in AGCT. As the FOXL2 C134W mutation is present in essentially all AGCTs and telomerase reactivation is required for tumorigenesis, it is likely that additional mutations are responsible for the variability in clinical behaviour. This study aims to describe the mutational landscape of AGCT to further refine our understanding of the frequent recurrence of this disease. METHODS: Using whole genome sequencing (WGS), we characterized the genomes of ten AGCTs and their matched normal blood. We observed that AGCTs have a low mutation burden and the majority of mutations are single nucleotides variants. We have collected 516 formalin-fixed paraffin-embedded AGCT specimens including primary, recurrent and metastatic tumors from seven international centres for validation of our WGS results. Allelic discrimination assays were used for hotspots mutations, in addition to targeted sequencing of 39 genes of interest using a custom amplicon-based panel in our extension cohort. RESULTS: Of the 39 genes analyzed, the third most commonly mutated gene (FOXL2 and TERT being the first and second most common) in our preliminary analysis of 88 cases was lysine (K)-specific methyltransferase 2D (KMT2D or MLL2). We identified various missense and nonsense mutations in this gene in 16 of 88 AGCTs (18%) analyzed thus far. KMT2D is a histone methyltransferase that targets histone H3 lysine 4 (H3K4), a methylation activation mark, and has an essential role in transcriptional regulation. Using an allelic discrimination assay, we identified a known hotspot mutation (c.49G>A;p.E17K) in v-akt murine thymoma viral oncogene 1 (AKT1) in 2 of 67 (3%) AGCT patients, one of which the mutation was present in all three recurrent specimens from the same patient. AKT1 E17K mutation has been reported in multiple cancers such as breast, colorectal and high grade serous ovarian cancer at a low prevalence. A recent clinical trial of AKT inhibition in solid tumors with AKT1 mutations included one recurrent AGCT patient and showed significant tumor regression in one metastatic site. CONCLUSION: AKT1 E17K mutations are present in AGCT at a low prevalence and could represent a therapeutic target for patients with recurrent advanced stage disease harbouring this mutation. Citation Format: Jessica A. Pilsworth, Dawn R. Cochrane, Samantha Neilson, Anniina E.M. Färkkilä, Hugo M. Horlings, Satoshi Yanagida, Janine Senz, Yi Kan Wang, Bahar Moussavi, Daniel Lai, Ali Bashashati, Jacqueline Keul, Adele Wong, Hannah van Meurs, Sara Y. Brucker, Florin-Andrei Taran, Bernhard Krämer, Annette Staebler, Esther Oliva, Sohrab P. Shah, Stefan Kommoss, Friedrich Kommoss, C. Blake Gilks and David G. Huntsman. GENOMIC CHARACTERIZATION OF ADULT-TYPE GRANULOSA CELL TUMORS: IMPLICATIONS FOR PATHOGENESIS AND TREATMENT OF RECURRENT DISEASE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-047.

A 53-year-old woman presented with a right nipple non-pruritic lesion of 7 years’ duration, which has been slowly growing over the few months. There was no associated nipple discharge or breast lump. The patient denied any previous breast surgery or trauma. On examination, there was a non-tender

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified in multiple cancers, such as melanoma and glioblastoma, as gain-of-function mutations that promote transcriptional activation of TERT. A recent study investigating TERT promoter mutations in ovarian carcinomas found mutations in 15% of clear cell carcinomas. However, it is unknown whether these mutations are prevalent in adult-type granulosa cell tumors (AGCTs) of the ovary, Sertoli-Leydig cell tumors (SLCTs), and other malignant sex cord-stromal tumors. We performed whole-genome sequencing on ten AGCT cases with matched normal and identified the TERT C228T promoter mutation in 50% of cases. We found that AGCT cases with mutated TERT promoter have increased expression of TERT mRNA compared to those with wild-type TERT promoter. All five TERT promoter mutated cases had high levels of TERT mRNA expression, whereas three of the five wild-type TERT cases had no measurable TERT mRNA expression. There was a tendency towards longer telomere lengths in AGCT cases with the TERT promoter mutation relative to those without, although it was not statistically significant. These results suggest that telomerase may be activated by a different method in the cases with no TERT promoter mutations but have TERT mRNA expression. The remaining cases with neither TERT promoter mutations nor TERT mRNA expression likely maintain their telomeres using a telomerase-independent method, such as the alternative lengthening of telomeres pathway. TERT C228T allelic discrimination analysis of 331 AGCTs, 5 SLCTs, and 18 other malignant sex cord-stromal tumors detected the mutation in 56/247 (23%) of primary AGCTs, 22/84 (26%) of recurrent AGCTs, 1/5 (20%) of SLCTs and (0/18) 0% of other malignant sex cord-stromal tumors. The single SLCT case with the TERT promoter mutation was poorly differentiated and harbored the pathognomonic FOXL2 mutation of AGCT, suggesting this SLCT case may actually be an AGCT. In 204 AGCT cases with available survival data, there was a trend towards worse disease-specific survival in patients with the TERT promoter mutation compared to those without; however, statistical significance was not reached (p = 0.128, log-ranked test). In 5 AGCT cases with primary and recurrent tissues, we found that the TERT promoter mutation was absent in the primary tumors but present in the recurrent tumors, suggesting that TERT C228T mutation may play an active role in progression of AGCTs. Overall, we found that TERT C228T promoter mutation was most common in AGCTs among the different malignant sex cord-stromal tumors. Our data confirm the activation of telomerase in AGCTs via TERT C228T promoter mutation, although alternative telomerase activation methods in AGCTs may exist. Our results suggest that TERT activation may play a role in AGCT recurrence. As such, telomere biology may be important for the progression of AGCTs. This abstract is also being presented as Poster B54. Citation Format: Jessica A. Pilsworth, Dawn R. Cochrane, Zhouchunyang Xia, Geraldine Aubert, Anniina E. M. Färkkilä, Hugo M. Horlings, Satoshi Yanagida, Winnie Yang, Jamie L. P. Lim, Yikan Wang, Ali Bashashati, Jacqueline Keul, Adele Wong, Esther Oliva, Sohrab P. Shah, Stefan Kommoss, Friedrich Kommoss, Peter M. Lansdorp, Duncan M. Baird, David G. Huntsman. TERT is frequently mutated in adult-type granulosa cell tumors of the ovary compared to other malignant sex cord-stromal tumors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR13.

Objective Somatic POLE mutations have been found in a subset of endometrioid ECs particularly in FIGO grade 3 tumors while POLD1 mutations are reportedly rare in ECs. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to determine the mutation spectrum of somatic and germline POLE and POLD1 gene mutations in South East Asian (SEA) women with FIGO grade 3 endometrioid ECs. Methods Forty-seven patients diagnosed with FIGO grade 3 endometrioid EC, diagnosed between 2009 and 2013 were included. Next generation sequencing (NGS) using formalin fixed embedded (FFPE) tissue was utilized to sequence tumor and matched normal tissue. Tumors were also assessed for other clinicopathologic and microsatellite status phenotype. Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan–Meier method. Results Pathogenic POLE (somatic or germline) and POLD1 (germline) mutations were detected in 29.7% (14/47) and 4.3% (2/47) patients, respectively. Three pathogenic germline mutations; one POLE and two POLD1 mutations were novel. Pathogenic germline and somatic POLE and POLD1 mutations were associated with 100% recurrence free survival. In contrast, among the wild-type POLE and POLD1 patients, 25% (8/32) had recurrence with 15.6% (5/32) subsequently dying of the disease. Somatic POLE -mutated tumors were more commonly associated with microsatellite stable (MSS) ECs (83% vs 49%; p=0.04) and peritumoral lymphocytic infiltration (75% vs 42%; p=0.05). All tumors with tumoral infiltrating lymphocytes exhibited peritumoral lymphocytic infiltrate but not vice versa. Conclusion Mutations in POLE and POLD1 in SEA women with grade 3 endometrioid ECs are associated with improved recurrence free survival. Notably, germline mutations in either POLE / POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes. MSS and peritumoral lymphocytic infiltration may be useful histological features for distinguishing POLE mutated grade 3 endometrioid ECs.

Introduction: Endometrial carcinoma (EC) is the most common gynaecological cancer in developed countries. Mortality rates of patients with FIGO grade 3 endometrioid ECs are almost similar to that of uterine serous carcinoma and clear cell carcinoma. In 2013, the Cancer Tumour Genome Atlast (TGCA) identified POLE gene mutations in a subset of ECs, predominantly in the endometrioid subtype with high FIGO grade. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to evaluate the association between the POLE gene mutations and progression free survival in Asian women with FIGO grade 3 endometrioid EC. Methods: Forty-five Asian patients diagnosed with FIGO Grade 3 endometrioid EC between 2009 and 2013 were included. Next generation sequencing (NGS) performed utilizing the Ion Torrent Personal Genome Machine (PGM) and custom designed AmpliSeq panel for formalin fixed embedded (FFPE) tissue was performed. Using the Ion Reporter, mutations with at least 10% allele frequency and present in the COSMIC database were deemed to be pathogenic. All other mutations, excluding silent mutations, were considered as variants of unknown significance (VUS). Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan-Meier method and compared using logrank test. Results: All detected pathogenic and VUS POLE gene mutations were missense mutations. Our results provide further evidence to corroborate the mutation effect of POLE gene with 100% recurrence free survival in FIGO Grade 3 endometrioid EC patients with pathogenic POLE gene mutations, extends to South East Asian women as well (median follow-up POLE vs wild type; 52.5 vs 45; p = 0.2). Pathogenic somatic POLE gene mutations were present in 25.5% (12/45) patients with Grade 3 endometrioid EC. All were still alive at the time of censure with no reports of relapse following initial treatment. Three of these women harbored mutations outside exons 9 to 14 with one mutation listed as pathogenic in colorectal carcinomas. Among women without the pathogenic somatic POLE mutation, recurrence was seen in 24.2% (8/33) with 15.1% (5/33) subsequently dying of the disease. Conclusion: POLE gene mutations confer a good prognosis for FIGO grade 3 endometrioid EC and will be important in clinical decision making. POLE wild-type patients potentially show have closer follow-up and should be considered for newer targeted chemotherapeutic agents. Citation Format: Adele Wong, Chik Hong Kuick, Wai Loong Wong, Jill M. Tham, Sorsiah Mansor, Loh Eva, Sudhanshi Jain, Sock Hoai Chan, Sze Huey Tan, Shao Tzu Li, Nadkarni N. Vikas, Sung Hock Chew, Joanne Ngeow, Wanjin Hong. POLE gene mutations confer good progression free survival in Asian women with FIGO grade 3 endometrioid endometrial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1793.