- Email: [email protected]
Mutational landscapes and tumour mutational burden expression in endometrial cancer
abstracts
(institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.
1039P
K. Hasegawa1, K. Taniguchi2, S. Sato1, A. Yoshinaga2, M. Tsugane2, M. Nishiyama3, K. Fujiwara1 1 Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan, 2Yakult Central Institute, Yakult Honsha Co., Ltd., Kunitachi, Japan, 3 Molecular and Cellular Pharmacology and Oncology, Gunma University, Maebashi, Japan Background: The signal transducer and activator of transcription (STAT) 3 plays a critical role in the regulation of cell growth, metastasis, and survival. STAT3 signaling is constitutively activated in various cancers including gynecological cancers. We evaluated the efficacy of a novel selective STAT3 inhibitor, YHO-1701, ex vivo and in vivo for ovarian and endometrial cancer. Methods: An expression profile of YHO-1701 treated cells was compared with that of other STAT3 inhibitors or its upstream Janus kinase inhibitor by RNA sequencing. The downstream signaling of YHO-1701 was investigated by western blot. Patients derived primary cancer cells (PDCs) were isolated from surgical specimens or ascites cells from ovarian or endometrial cancer patients, and the growth inhibitory effect of YHO-1701 on PDCs was evaluated by standard colorimetric assays. Antitumor activity of YHO1701 was assessed using an SKOV3 abdominal dissemination xenograft model. Results: We investigated the specificity of YHO-1701 by pathway analysis using RNA sequencing results of the cells treated with or without each inhibitor and found YHO1701 regulated STAT3 signaling more tightly than others did. We confirmed decreased levels of pSTAT3 S727, Survivin, and c-Myc in the cells treated with YHO-1701. A total of 41 PDCs were treated with YHO-1701 and showed a remarkable growth inhibition compared with the control group (P < 0.0007 and P < 0.0001 for ovarian and endometrial cancer cells, respectively). We tested the potential antitumor activity of orally administrated YHO-1701 in a mouse intraperitoneal dissemination model of ovarian cancer using SKOV3. We observed decreased numbers of peritoneal metastasis in mice treated with YHO-1701 compared with those treated with vehicle control (P < 0.05). Conclusions: Our results demonstrated the efficacy of YHO-1701 for ovarian and endometrial cancer both ex vivo and in vivo through STAT3 signaling. Legal entity responsible for the study: The authors. Funding: Yakult Honsha. Disclosure: K. Hasegawa: Research grant / Funding (self): Yakult. K. Taniguchi: Full / Part-time employment: Yakult. A. Yoshinaga: Full / Part-time employment: Yakult. M. Tsugane: Full / Part-time employment: Yakut. All other authors have declared no conflicts of interest.
1040P 1038P
The feasibility and efficacy of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian insufficiency in patient with malignant ovarian germ cell tumours
M.K. Kim Obstetrics and Gynecology, Samsung Changwon Hospital Sung Kyun Kwan University, Changwon, Republic of Korea Background: To assess the effects of a gonadotropin-releasing hormone agonists (GnRHa) administration in young patients with malignant ovarian germ cell tumour (MOGCT) during chemotherapy on the prevention of chemotherapy-induced ovarian insufficiency. Methods: This multicenter, retrospective study was conducted at fifteen sites in Korea and enrolled 354 patients between January 1995 and January 2018. Among them 227 patients were included in this study according the inclusion criteria: 1) patients diagnosed as pathologically malignant germ cell tumours of the ovaries, 2) who have preserved the uterus and at least one ovary, 3) who received postoperative chemotherapy at least 3 cycles, 4) age at diagnosis, after menarche < 40 years old, 5) available clinical information on menstrual resumption. Patients were divided into two groups according to the use of GnRHa during chemotherapy (GnRHa group and non-GnRHa group) and compared the incidence of early menopause. Results: There was no difference in age, parity, menarche, stage, and type of operation (unilateral or bi-lateral adnexal surgery) among the two groups. The distribution of histology and types of chemotherapy drugs were different. After the end of chemotherapy, the resumption of menstruation was 100% in GnRHa group and 91% in non-GnRHa group (p ¼ 0.0132). The univariate analysis of the factors affecting menstrual resumption showed that the use of GnRHa during chemotherapy was statistically significant difference (OR, 0.00 (00.69;95% CI, p ¼ 0.013). Conclusions: The present findings provide evidence for the efficacy of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced ovarian insufficiency and potentially improve fertility in young patients with MOGCT. Legal entity responsible for the study: The author. Funding: CHA Bundang Medical Centre. Disclosure: The author has declared no conflicts of interest.
v424 | Gynaecological Cancers
Ex vivo cytotoxicity and in vivo anti-tumour activity of a novel highly selective STAT3 inhibitor YHO-1701 for ovarian and endometrial cancer
Mutational landscapes and tumour mutational burden expression in endometrial cancer
Y. Zhang1, J. Zhang1, Z. Shao1, L. Zhao1, Y. Zhang2, S. Zhang2, S. Zhao3, F. Guo2, F. Pang2, L. Zhang2, X. Dong4, K. Wang3 1 Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China, 2 Medical Liaison Department, OrigiMed, Shanghai, China, 3Bioinformatics, OrigiMed, Shanghai, China, 4Clinical Pathology Department, OrigiMed, Shanghai, China Background: Endometrial cancer (EC) is one of the most common gynaecological tumours. Tumour mutational burden (TMB) has emerged as a promising predictor to evaluate efficacy to immunotherapy in several kinds of solid tumours. However, the relationship between TMB and genetic features of EC remains unclear. Methods: Total 50 EC patients including 41 endometrioid adenocarcinoma, 6 uterine serous adenocarcinoma, 1 uterine clear cell carcinoma, 1 endometrial squamous cell carcinoma and 1 endometrial adenosquamous carcinoma were enrolled in this study. The ECs had been classified as FIGO I (n ¼ 14), II (n ¼ 6), III (n ¼ 12), IV (n ¼ 16) and not available (n ¼ 2). FFPE tumour and matched blood samples were collected from patients for NGS-based targeted panel sequencing (450 genes). Genomic alterations and TMB were assessed. Results: The 50 patients had a median age of 56 years (range, 32-73 years) with a median TMB of 3.8 muts/Mb (interquartile range (IQR), 1.5-13.7 muts/Mb). We found recurrent mutations, including PTEN (64%), PIK3CA (44%), ARID1A (40%), PIK3R1 (36%), TP53 (32%), CHD4 (20%), and KRAS (20%). FGFR2 mutations were occurred in 7 (14%) patients. The most frequently mutated genes in early-stage (FIGO I and II) were PTEN (85%), ARID1A (50%), PIK3R1 (50%), PIK3CA (40%), LRP1B (30%), and CHD4 (30%), while the most common mutations in advanced-stage (FIGO III and IV) were PTEN (46%), PIK3CA (43%), TP53 (43%), ARID1A (36%), PIK3R1 (29%), and KRAS (21%). We also found that all POLE mutations (5/5) occurred in early-stage. Mutations of PIK3R1, CHD4, CTCF, SETD2, PPP2R1A, NF1, BRCA2, ARID1B and POLE were associated with TMB-high (TMB-H, TMB10muts/ Mb) (P < 0.05 for all). Importantly, all POLE mutations occurred in EC with TMB-H, including two cases of EC with ultrahigh TMB (TMB > 100 muts/Mb). At least one actionable mutation was identified in 86% (43/50) patients. Conclusions: PI3K signaling pathway genes, PTEN, PIK3CA and PIK3R1 were most frequently mutated in EC. 26% patients (13/50) had TMB-H. POLE mutations likely occurred in early stage and were related with TMB-H, which may provide potential targets for immunotherapy of EC. Legal entity responsible for the study: The authors.
Volume 30 | Supplement 5 | October 2019
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Methods: Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar modelbuilding strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings. Results: The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found. Conclusions: An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM. Clinical trial identification: 2011-006288-23. Legal entity responsible for the study: ARCAGY-GINECO. Funding: Boehringer Ingelheim. Disclosure: N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding
Annals of Oncology
abstracts
Annals of Oncology Funding: National Natural Science Foundation of China (Youth fund project, no. 81602267). Disclosure: Y. Zhang: Full / Part-time employment: OrigiMed. S. Zhang: Full / Part-time employment: OrigiMed. S. Zhao: Full / Part-time employment: OrigiMed. F. Guo: Full / Part-time employment: OrigiMed. F. Pang: Full / Part-time employment: OrigiMed. L. Zhang: Full / Part-time employment: OrigiMed. X. Dong: Full / Part-time employment: OrigiMed. K. Wang: Full / Part-time employment: OrigiMed. All other authors have declared no conflicts of interest.
1041P
Conclusions: WATi was present in nearly 50% of newly diagnosed EC patients regardless of stage. There was an association between the presence and severity of WATi and BMI among patients with EC. Specifically, WATi was associated with hyperglycemia, hypertension, and diabetes mellitus. Further investigation into the impact of WATi on the tumor microenvironment and patient outcomes is ongoing. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Clinical features and frequency of mismatch repair protein deficiency in ovarian clear cell and endometrioid carcinoma patients
Background: The rates of mismatch repair (MMR) protein deficiency and microsatellite instability (MSI) in ovarian clear cell (CC) and endometrioid (EM) cancer patients were investigated. The clinical features of CC and EM were also analyzed. Methods: Patients postoperatively diagnosed as CC or EM carcinoma from January 2006 to December 2015 were eligible. Diagnosis of all cases was confirmed by the Central Pathological Review Board. MMR protein was analyzed by IHC using a monoclonal antibody and MSI was examined by a multiplex PCR assay for five microsatellite markers, BAT25, BAT26, NR-21, NR-24, and MONO-27. MLH1 IHC-negative cases were examined for DNA hypermethylation of the MLH1 promoter. Results: We enrolled 339 cases consisting of 219 CC, 116 EM and 4 mixed type (MT) cases. One case could not be evaluated by IHC. MMR protein deficiency was confirmed in five CC (2.3%), 16 EM (13.9%) and 1 MT case (25%). Deficiency was observed in 4 cases for MLH1 and PMS2, in 13 cases for MSH2 and MSH6, in 1 case for MSH2 and PMS2, in 2 cases for MSH6, and in 1 case for PMS2. DNA hypermethylation of the MLH1 promoter was detected in one of the four MLH1 and PMS2 deficiency cases. Three of the 339 cases could not be evaluated by MSI. A high rate of MSI was confirmed in 13 cases (3.9%) and MMR deficiency was detected by IHC in these cases. However, MSI was not detected in the other nine cases where MMR deficiency was detected by IHC. The median age of all 339 cases was 54 (CC 54, EM 51) and that of CC and EM cases with MMR deficiency was 39 and 48 years, respectively. Conclusions: The rate of MMR deficiency in CC and EM was not high, whereas CC in young women was more frequent. IHC is a more successful screening method of MMR deficiency in ovarian CC and EM compared with MSI detection. The rate of MLH1 promoter hypermethylation (epigenetic MMR deficiency) in ovarian CC and EM was less than that of endometrial cancer. Legal entity responsible for the study: The author. Funding: National Hospital Organization of Japan. Disclosure: The author has declared no conflicts of interest.
1042P
Prospective study evaluating white adipose tissue inflammation and clinicopathologic features in endometrial cancer
L.A. Moukarzel1, A. Stylianou1, M. Wu1, S.P. Nobre1, N.R. Abu-Rustum1, V. Broach1, D.D. Giri2, N.M. Iyengar3, B. Weigelt2, V. Makker3 1 Surgery Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 3Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York City, NY, USA Background: Obesity is a chief mediator of endometrial cancer (EC) and is responsible for the increasing incidence and mortality of this malignancy. Obesity induced chronic inflammation, creates a pro-neoplastic environment via local and systemic processes. In other obesity-related cancers, white adipose tissue inflammation (WATi) is an independent predictor of shortened cancer-specific survival. A retrospective study in advanced EC revealed that WATi is associated with shorter progression-free survival. The aim of this prospective study was to investigate the presence of WATi in EC and to evaluate the relationship between WATi and clinicopathologic factors in women with EC. Methods: Patients who underwent primary surgical management of EC, regardless of stage or histology, had omental biopsies collected. WATi was detected by the presence of dead/dying adipocytes surrounded by CD68þ macrophages forming a crown-like structure (CLS). Clinicopathologic data were extracted from medical records. For association with WATi, Wilcoxon rank sum test was used for continuous variables, and the Fisher’s exact or v2 test for categorical variables. Results: A total of 101 EC patients who underwent primary surgical management between 2015 and 2019 were included. Of these, 46 (46%) had WATi. The presence of WATi was unaffected by race, histology, FIGO stage, smoking or menopausal state. In contrast, dyslipidemia (39% vs 13%, p ¼ 0.002), hypertension (70% vs 35%, p < 0.001) and diabetes mellitus (13% vs 9%, p ¼ 0.015) were significantly more frequent in EC patients with WATi. The median BMI was 35 kg/m2 and 29 kg/m2 in the WATi versus non WATi patients, respectively (p < 0.001). The median CLS based on BMI was 0.19 CLS/cm2 for those with a BMI of < 25kg/m2, 0.34 CLS/cm2 for those with a BMI of 2529kg/m2, and 1.01 CLS/cm2 for those with a BMI of > 30kg/m2.
Volume 30 | Supplement 5 | October 2019
Cancer-specific survival with or without adjuvant chemotherapy in high-risk stage I endometrial cancer
J. Ko1, B. Lester2, N. Le3, G. Bowering1, C. Rugayan2, A. Kumar4 Medical Oncology, BC Cancer - Abbotsford, Abbotsford, BC, Canada, 2Radiation Oncology, BC Cancer - Abbotsford, Abbotsford, BC, Canada, 3Biostatistics, BC Cancer Research Centre, Vancouver, BC, Canada, 4Medical Oncology, BC Cancer - Surrey, Surrey, BC, Canada
1
Background: Controversies exist for utility of adjuvant chemotherapy (AC) in early stage high risk endometrial cancer (EC). Our study sought to evaluate overall, relapsefree and cancer-specific survivals (OS, RFS, CSS) in patients with high risk FIGO stage I EC. Methods: Per provincial guideline, high risk stage I EC eligible for AC was defined as 1) endometrioid histology, stage IB and grade 3 or 2) non-endometrioid histology with any myometrial invasion. We identified all consecutive patients with stage I EC from 6 cancer centres in British Columbia, Canada diagnosed between 2000 and 2010. CSS was defined as time between diagnosis and death due to endometrial cancer. Descriptive statistics were used to evaluate patient, disease and treatment characteristics; Cox proportional hazard regression was used to evaluate differences in OS, RFS and CSS. Results: Among stage I EC (n ¼ 1426), 24 with endometrioid histology and 214 with non-endometrioid histology with high risk characteristics were identified (n ¼ 238). Median age was 66 (range 33-91); stage IA ¼ 196, IB ¼ 50; grade 1¼16, 2¼20, 3¼196; LVIþ 88. Among all high risk patients, OS (RR 0.37, 95% CI 0.20-0.71, p ¼ 0.002; median 6.3 vs 12.2 years) and RFS (RR 0.35, 95% CI 0.19-0.65, p ¼ 0.001; median 5.6 vs 12.2 years) were significantly better in patients who received AC, but CSS (RR 0.65, 95% CI 0.32-1.33, p ¼ 0.24; median not reached in both groups) was not statistically improved although numerically favoured AC. Similarly, among non-endometrioid histology, OS (RR 0.40, 95% CI 0.20-0.78, p ¼ 0.008; median 6.4 vs 12.2 years) and RFS (RR 0.38, 95% CI 0.20-0.72, p ¼ 0.03; median 5.9 vs 12.2 years) were significantly better in patients who received AC, but improvements in CSS with AC (RR 0.68, 95% CI 0.31.4, p ¼ 0.32; median not reached in both groups) were not statistically significant. Conclusions: Despite its use, there is insufficient evidence that AC reduces risk of death due to cancer in high risk stage I EC, although DSS is numerically improved in patients who received AC. Improvements in OS and RFS associated with chemotherapy may be largely attributed to other confounding factors. Future prospective studies are needed to clarify the role of contemporary AC in high risk stage I EC. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1044P
Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study
D. O’Malley1, A. Marabelle2, A. De Jesus-Acosta3, S.A. Piha-Paul4, A. Arkhipov5, F. Longo6, D. Motola-Kuba7, R. Shapira-Frommer8, R. Geva9, B.J. Rimel10, J.A. LopezMartin11, A.R. Hansen12, J.M. Mehnert13, X. Chen14, F. Jin14, K. Norwood14, P.A. Ott15 1 Ob/gyn, The Ohio State University James Cancer Hospital, Columbus, OH, USA, 2Drug Development Department, Institut Gustave Roussy, Villejuif, France, 3Medical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA, 4Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA, 5 Chemotherapy and Radiotherapy Department, Federal State Autonomous Institution “Treatment and Rehabilitation Center” of the Ministry of Health of Russian Federation, Moscow, Russian Federation, 6Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain, 7Clinical Investigation, COMOP A.C., Mexico City, Mexico, 8Oncology, Chaim Sheba Medical Centre, Ramat Gan, Israel, 9Division of Oncology, Tel Aviv Sourasky Medical Center-(Ichilov), Tel Aviv, Israel, 10Gynecology-Oncology, Cedars-Sinai Medical Centre, Los Angeles, CA, USA, 11Medical Oncology, 12 de Octubre University Hospital & Research Institute (i þ 12), Madrid, Spain, 12Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada, 13Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA, 14MRL, Merck & Co., Inc., Kenilworth, NJ, USA, 15Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA Background: Pembrolizumab (pembro) provides durable responses in patients (pts) with MSI-H cancers and is approved in the US/Japan for the treatment of MSI-H advanced solid tumors. MSI-H is expressed in 25% of endometrial cancers. An analysis of pts with MSI-H advanced endometrial cancer enrolled in cohorts D (advanced
doi:10.1093/annonc/mdz250 | v425
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1043P K. Takehara Gynecologic Oncology, Shikoku Cancer Center, Matsuyama, Japan
(institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.
1039P
K. Hasegawa1, K. Taniguchi2, S. Sato1, A. Yoshinaga2, M. Tsugane2, M. Nishiyama3, K. Fujiwara1 1 Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan, 2Yakult Central Institute, Yakult Honsha Co., Ltd., Kunitachi, Japan, 3 Molecular and Cellular Pharmacology and Oncology, Gunma University, Maebashi, Japan Background: The signal transducer and activator of transcription (STAT) 3 plays a critical role in the regulation of cell growth, metastasis, and survival. STAT3 signaling is constitutively activated in various cancers including gynecological cancers. We evaluated the efficacy of a novel selective STAT3 inhibitor, YHO-1701, ex vivo and in vivo for ovarian and endometrial cancer. Methods: An expression profile of YHO-1701 treated cells was compared with that of other STAT3 inhibitors or its upstream Janus kinase inhibitor by RNA sequencing. The downstream signaling of YHO-1701 was investigated by western blot. Patients derived primary cancer cells (PDCs) were isolated from surgical specimens or ascites cells from ovarian or endometrial cancer patients, and the growth inhibitory effect of YHO-1701 on PDCs was evaluated by standard colorimetric assays. Antitumor activity of YHO1701 was assessed using an SKOV3 abdominal dissemination xenograft model. Results: We investigated the specificity of YHO-1701 by pathway analysis using RNA sequencing results of the cells treated with or without each inhibitor and found YHO1701 regulated STAT3 signaling more tightly than others did. We confirmed decreased levels of pSTAT3 S727, Survivin, and c-Myc in the cells treated with YHO-1701. A total of 41 PDCs were treated with YHO-1701 and showed a remarkable growth inhibition compared with the control group (P < 0.0007 and P < 0.0001 for ovarian and endometrial cancer cells, respectively). We tested the potential antitumor activity of orally administrated YHO-1701 in a mouse intraperitoneal dissemination model of ovarian cancer using SKOV3. We observed decreased numbers of peritoneal metastasis in mice treated with YHO-1701 compared with those treated with vehicle control (P < 0.05). Conclusions: Our results demonstrated the efficacy of YHO-1701 for ovarian and endometrial cancer both ex vivo and in vivo through STAT3 signaling. Legal entity responsible for the study: The authors. Funding: Yakult Honsha. Disclosure: K. Hasegawa: Research grant / Funding (self): Yakult. K. Taniguchi: Full / Part-time employment: Yakult. A. Yoshinaga: Full / Part-time employment: Yakult. M. Tsugane: Full / Part-time employment: Yakut. All other authors have declared no conflicts of interest.
1040P 1038P
The feasibility and efficacy of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian insufficiency in patient with malignant ovarian germ cell tumours
M.K. Kim Obstetrics and Gynecology, Samsung Changwon Hospital Sung Kyun Kwan University, Changwon, Republic of Korea Background: To assess the effects of a gonadotropin-releasing hormone agonists (GnRHa) administration in young patients with malignant ovarian germ cell tumour (MOGCT) during chemotherapy on the prevention of chemotherapy-induced ovarian insufficiency. Methods: This multicenter, retrospective study was conducted at fifteen sites in Korea and enrolled 354 patients between January 1995 and January 2018. Among them 227 patients were included in this study according the inclusion criteria: 1) patients diagnosed as pathologically malignant germ cell tumours of the ovaries, 2) who have preserved the uterus and at least one ovary, 3) who received postoperative chemotherapy at least 3 cycles, 4) age at diagnosis, after menarche < 40 years old, 5) available clinical information on menstrual resumption. Patients were divided into two groups according to the use of GnRHa during chemotherapy (GnRHa group and non-GnRHa group) and compared the incidence of early menopause. Results: There was no difference in age, parity, menarche, stage, and type of operation (unilateral or bi-lateral adnexal surgery) among the two groups. The distribution of histology and types of chemotherapy drugs were different. After the end of chemotherapy, the resumption of menstruation was 100% in GnRHa group and 91% in non-GnRHa group (p ¼ 0.0132). The univariate analysis of the factors affecting menstrual resumption showed that the use of GnRHa during chemotherapy was statistically significant difference (OR, 0.00 (00.69;95% CI, p ¼ 0.013). Conclusions: The present findings provide evidence for the efficacy of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced ovarian insufficiency and potentially improve fertility in young patients with MOGCT. Legal entity responsible for the study: The author. Funding: CHA Bundang Medical Centre. Disclosure: The author has declared no conflicts of interest.
v424 | Gynaecological Cancers
Ex vivo cytotoxicity and in vivo anti-tumour activity of a novel highly selective STAT3 inhibitor YHO-1701 for ovarian and endometrial cancer
Mutational landscapes and tumour mutational burden expression in endometrial cancer
Y. Zhang1, J. Zhang1, Z. Shao1, L. Zhao1, Y. Zhang2, S. Zhang2, S. Zhao3, F. Guo2, F. Pang2, L. Zhang2, X. Dong4, K. Wang3 1 Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China, 2 Medical Liaison Department, OrigiMed, Shanghai, China, 3Bioinformatics, OrigiMed, Shanghai, China, 4Clinical Pathology Department, OrigiMed, Shanghai, China Background: Endometrial cancer (EC) is one of the most common gynaecological tumours. Tumour mutational burden (TMB) has emerged as a promising predictor to evaluate efficacy to immunotherapy in several kinds of solid tumours. However, the relationship between TMB and genetic features of EC remains unclear. Methods: Total 50 EC patients including 41 endometrioid adenocarcinoma, 6 uterine serous adenocarcinoma, 1 uterine clear cell carcinoma, 1 endometrial squamous cell carcinoma and 1 endometrial adenosquamous carcinoma were enrolled in this study. The ECs had been classified as FIGO I (n ¼ 14), II (n ¼ 6), III (n ¼ 12), IV (n ¼ 16) and not available (n ¼ 2). FFPE tumour and matched blood samples were collected from patients for NGS-based targeted panel sequencing (450 genes). Genomic alterations and TMB were assessed. Results: The 50 patients had a median age of 56 years (range, 32-73 years) with a median TMB of 3.8 muts/Mb (interquartile range (IQR), 1.5-13.7 muts/Mb). We found recurrent mutations, including PTEN (64%), PIK3CA (44%), ARID1A (40%), PIK3R1 (36%), TP53 (32%), CHD4 (20%), and KRAS (20%). FGFR2 mutations were occurred in 7 (14%) patients. The most frequently mutated genes in early-stage (FIGO I and II) were PTEN (85%), ARID1A (50%), PIK3R1 (50%), PIK3CA (40%), LRP1B (30%), and CHD4 (30%), while the most common mutations in advanced-stage (FIGO III and IV) were PTEN (46%), PIK3CA (43%), TP53 (43%), ARID1A (36%), PIK3R1 (29%), and KRAS (21%). We also found that all POLE mutations (5/5) occurred in early-stage. Mutations of PIK3R1, CHD4, CTCF, SETD2, PPP2R1A, NF1, BRCA2, ARID1B and POLE were associated with TMB-high (TMB-H, TMB10muts/ Mb) (P < 0.05 for all). Importantly, all POLE mutations occurred in EC with TMB-H, including two cases of EC with ultrahigh TMB (TMB > 100 muts/Mb). At least one actionable mutation was identified in 86% (43/50) patients. Conclusions: PI3K signaling pathway genes, PTEN, PIK3CA and PIK3R1 were most frequently mutated in EC. 26% patients (13/50) had TMB-H. POLE mutations likely occurred in early stage and were related with TMB-H, which may provide potential targets for immunotherapy of EC. Legal entity responsible for the study: The authors.
Volume 30 | Supplement 5 | October 2019
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Methods: Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar modelbuilding strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings. Results: The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found. Conclusions: An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM. Clinical trial identification: 2011-006288-23. Legal entity responsible for the study: ARCAGY-GINECO. Funding: Boehringer Ingelheim. Disclosure: N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding
Annals of Oncology
abstracts
Annals of Oncology Funding: National Natural Science Foundation of China (Youth fund project, no. 81602267). Disclosure: Y. Zhang: Full / Part-time employment: OrigiMed. S. Zhang: Full / Part-time employment: OrigiMed. S. Zhao: Full / Part-time employment: OrigiMed. F. Guo: Full / Part-time employment: OrigiMed. F. Pang: Full / Part-time employment: OrigiMed. L. Zhang: Full / Part-time employment: OrigiMed. X. Dong: Full / Part-time employment: OrigiMed. K. Wang: Full / Part-time employment: OrigiMed. All other authors have declared no conflicts of interest.
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Conclusions: WATi was present in nearly 50% of newly diagnosed EC patients regardless of stage. There was an association between the presence and severity of WATi and BMI among patients with EC. Specifically, WATi was associated with hyperglycemia, hypertension, and diabetes mellitus. Further investigation into the impact of WATi on the tumor microenvironment and patient outcomes is ongoing. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Clinical features and frequency of mismatch repair protein deficiency in ovarian clear cell and endometrioid carcinoma patients
Background: The rates of mismatch repair (MMR) protein deficiency and microsatellite instability (MSI) in ovarian clear cell (CC) and endometrioid (EM) cancer patients were investigated. The clinical features of CC and EM were also analyzed. Methods: Patients postoperatively diagnosed as CC or EM carcinoma from January 2006 to December 2015 were eligible. Diagnosis of all cases was confirmed by the Central Pathological Review Board. MMR protein was analyzed by IHC using a monoclonal antibody and MSI was examined by a multiplex PCR assay for five microsatellite markers, BAT25, BAT26, NR-21, NR-24, and MONO-27. MLH1 IHC-negative cases were examined for DNA hypermethylation of the MLH1 promoter. Results: We enrolled 339 cases consisting of 219 CC, 116 EM and 4 mixed type (MT) cases. One case could not be evaluated by IHC. MMR protein deficiency was confirmed in five CC (2.3%), 16 EM (13.9%) and 1 MT case (25%). Deficiency was observed in 4 cases for MLH1 and PMS2, in 13 cases for MSH2 and MSH6, in 1 case for MSH2 and PMS2, in 2 cases for MSH6, and in 1 case for PMS2. DNA hypermethylation of the MLH1 promoter was detected in one of the four MLH1 and PMS2 deficiency cases. Three of the 339 cases could not be evaluated by MSI. A high rate of MSI was confirmed in 13 cases (3.9%) and MMR deficiency was detected by IHC in these cases. However, MSI was not detected in the other nine cases where MMR deficiency was detected by IHC. The median age of all 339 cases was 54 (CC 54, EM 51) and that of CC and EM cases with MMR deficiency was 39 and 48 years, respectively. Conclusions: The rate of MMR deficiency in CC and EM was not high, whereas CC in young women was more frequent. IHC is a more successful screening method of MMR deficiency in ovarian CC and EM compared with MSI detection. The rate of MLH1 promoter hypermethylation (epigenetic MMR deficiency) in ovarian CC and EM was less than that of endometrial cancer. Legal entity responsible for the study: The author. Funding: National Hospital Organization of Japan. Disclosure: The author has declared no conflicts of interest.
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Prospective study evaluating white adipose tissue inflammation and clinicopathologic features in endometrial cancer
L.A. Moukarzel1, A. Stylianou1, M. Wu1, S.P. Nobre1, N.R. Abu-Rustum1, V. Broach1, D.D. Giri2, N.M. Iyengar3, B. Weigelt2, V. Makker3 1 Surgery Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 3Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York City, NY, USA Background: Obesity is a chief mediator of endometrial cancer (EC) and is responsible for the increasing incidence and mortality of this malignancy. Obesity induced chronic inflammation, creates a pro-neoplastic environment via local and systemic processes. In other obesity-related cancers, white adipose tissue inflammation (WATi) is an independent predictor of shortened cancer-specific survival. A retrospective study in advanced EC revealed that WATi is associated with shorter progression-free survival. The aim of this prospective study was to investigate the presence of WATi in EC and to evaluate the relationship between WATi and clinicopathologic factors in women with EC. Methods: Patients who underwent primary surgical management of EC, regardless of stage or histology, had omental biopsies collected. WATi was detected by the presence of dead/dying adipocytes surrounded by CD68þ macrophages forming a crown-like structure (CLS). Clinicopathologic data were extracted from medical records. For association with WATi, Wilcoxon rank sum test was used for continuous variables, and the Fisher’s exact or v2 test for categorical variables. Results: A total of 101 EC patients who underwent primary surgical management between 2015 and 2019 were included. Of these, 46 (46%) had WATi. The presence of WATi was unaffected by race, histology, FIGO stage, smoking or menopausal state. In contrast, dyslipidemia (39% vs 13%, p ¼ 0.002), hypertension (70% vs 35%, p < 0.001) and diabetes mellitus (13% vs 9%, p ¼ 0.015) were significantly more frequent in EC patients with WATi. The median BMI was 35 kg/m2 and 29 kg/m2 in the WATi versus non WATi patients, respectively (p < 0.001). The median CLS based on BMI was 0.19 CLS/cm2 for those with a BMI of < 25kg/m2, 0.34 CLS/cm2 for those with a BMI of 2529kg/m2, and 1.01 CLS/cm2 for those with a BMI of > 30kg/m2.
Volume 30 | Supplement 5 | October 2019
Cancer-specific survival with or without adjuvant chemotherapy in high-risk stage I endometrial cancer
J. Ko1, B. Lester2, N. Le3, G. Bowering1, C. Rugayan2, A. Kumar4 Medical Oncology, BC Cancer - Abbotsford, Abbotsford, BC, Canada, 2Radiation Oncology, BC Cancer - Abbotsford, Abbotsford, BC, Canada, 3Biostatistics, BC Cancer Research Centre, Vancouver, BC, Canada, 4Medical Oncology, BC Cancer - Surrey, Surrey, BC, Canada
1
Background: Controversies exist for utility of adjuvant chemotherapy (AC) in early stage high risk endometrial cancer (EC). Our study sought to evaluate overall, relapsefree and cancer-specific survivals (OS, RFS, CSS) in patients with high risk FIGO stage I EC. Methods: Per provincial guideline, high risk stage I EC eligible for AC was defined as 1) endometrioid histology, stage IB and grade 3 or 2) non-endometrioid histology with any myometrial invasion. We identified all consecutive patients with stage I EC from 6 cancer centres in British Columbia, Canada diagnosed between 2000 and 2010. CSS was defined as time between diagnosis and death due to endometrial cancer. Descriptive statistics were used to evaluate patient, disease and treatment characteristics; Cox proportional hazard regression was used to evaluate differences in OS, RFS and CSS. Results: Among stage I EC (n ¼ 1426), 24 with endometrioid histology and 214 with non-endometrioid histology with high risk characteristics were identified (n ¼ 238). Median age was 66 (range 33-91); stage IA ¼ 196, IB ¼ 50; grade 1¼16, 2¼20, 3¼196; LVIþ 88. Among all high risk patients, OS (RR 0.37, 95% CI 0.20-0.71, p ¼ 0.002; median 6.3 vs 12.2 years) and RFS (RR 0.35, 95% CI 0.19-0.65, p ¼ 0.001; median 5.6 vs 12.2 years) were significantly better in patients who received AC, but CSS (RR 0.65, 95% CI 0.32-1.33, p ¼ 0.24; median not reached in both groups) was not statistically improved although numerically favoured AC. Similarly, among non-endometrioid histology, OS (RR 0.40, 95% CI 0.20-0.78, p ¼ 0.008; median 6.4 vs 12.2 years) and RFS (RR 0.38, 95% CI 0.20-0.72, p ¼ 0.03; median 5.9 vs 12.2 years) were significantly better in patients who received AC, but improvements in CSS with AC (RR 0.68, 95% CI 0.31.4, p ¼ 0.32; median not reached in both groups) were not statistically significant. Conclusions: Despite its use, there is insufficient evidence that AC reduces risk of death due to cancer in high risk stage I EC, although DSS is numerically improved in patients who received AC. Improvements in OS and RFS associated with chemotherapy may be largely attributed to other confounding factors. Future prospective studies are needed to clarify the role of contemporary AC in high risk stage I EC. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
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Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study
D. O’Malley1, A. Marabelle2, A. De Jesus-Acosta3, S.A. Piha-Paul4, A. Arkhipov5, F. Longo6, D. Motola-Kuba7, R. Shapira-Frommer8, R. Geva9, B.J. Rimel10, J.A. LopezMartin11, A.R. Hansen12, J.M. Mehnert13, X. Chen14, F. Jin14, K. Norwood14, P.A. Ott15 1 Ob/gyn, The Ohio State University James Cancer Hospital, Columbus, OH, USA, 2Drug Development Department, Institut Gustave Roussy, Villejuif, France, 3Medical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA, 4Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA, 5 Chemotherapy and Radiotherapy Department, Federal State Autonomous Institution “Treatment and Rehabilitation Center” of the Ministry of Health of Russian Federation, Moscow, Russian Federation, 6Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain, 7Clinical Investigation, COMOP A.C., Mexico City, Mexico, 8Oncology, Chaim Sheba Medical Centre, Ramat Gan, Israel, 9Division of Oncology, Tel Aviv Sourasky Medical Center-(Ichilov), Tel Aviv, Israel, 10Gynecology-Oncology, Cedars-Sinai Medical Centre, Los Angeles, CA, USA, 11Medical Oncology, 12 de Octubre University Hospital & Research Institute (i þ 12), Madrid, Spain, 12Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada, 13Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA, 14MRL, Merck & Co., Inc., Kenilworth, NJ, USA, 15Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA Background: Pembrolizumab (pembro) provides durable responses in patients (pts) with MSI-H cancers and is approved in the US/Japan for the treatment of MSI-H advanced solid tumors. MSI-H is expressed in 25% of endometrial cancers. An analysis of pts with MSI-H advanced endometrial cancer enrolled in cohorts D (advanced
doi:10.1093/annonc/mdz250 | v425
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1043P K. Takehara Gynecologic Oncology, Shikoku Cancer Center, Matsuyama, Japan