High-throughput viable circulating tumor cell isolation using tapered-slit membrane filter-based chipsets in the differential diagnosis of ovarian tumors.

OBJECTIVE: To evaluate the diagnostic performance of circulating tumor cells (CTCs) using tapered-slit membrane filter (TSF)-based chipsets for the differential diagnosis of adnexal tumors. METHODS: A total of 230 women with indeterminate adnexal tumors were prospectively enrolled. The sensitivity, specificity, and accuracy of the CTC-detecting chipsets were analyzed according to postoperative pathological results and compared with those of cancer antigen (CA)-125 and imaging tests. RESULTS: Eighty-one (40.3%) benign tumors, 31 (15.4%) borderline tumors, and 89 (44.3%) ovarian cancers were pathologically confirmed. The sensitivity, specificity, and accuracy of CTC-detecting chipsets (75.3%, 58.0%, and 67.1%) for differentiating ovarian cancer from benign tumors were similar to CA-125 (78.7%, 53.1%, and 66.5%), but lower than CT/MRI (94.2%, 77.9%, and 86.5%). "CTC or CA125" showed increased sensitivity (91.0%) and "CTC and CA-125" revealed increased specificity (77.8%), comparable to CT/MRI. CTC detection rates in stage I/II and stage III/IV ovarian cancers were 69.6% and 81.4%, respectively. The sensitivity to detect high-grade serous (HGS) cancer from benign tumors (84.6%) was higher than that to detect non-HGS cancers (68.0%). CONCLUSION: Although the diagnostic performance of the TSF platform to differentiate between ovarian cancer and benign tumors did not yield significant results, the combination of CTC and CA-125 showed promising potential in the diagnostic accuracy of ovarian cancer.

Treatment outcomes according to various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia - Multicenter retrospective study (KGOG2033).

OBJECTIVE: To investigate pathologic complete response (pCR) and recurrence outcomes using various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN). METHODS: Medical records of patients diagnosed with AH/EIN and undergoing follow-up endometrial biopsy after progestin treatment between 2011 and 2020 were retrospectively reviewed. Clinical factors and treatment outcomes were analyzed according to initial progestin treatment (oral progestin [OP], levonorgestrel-releasing intrauterine device [LNG-IUD], and combination), OP dose, and maintenance treatment using Pearson's χ2, Fisher's exact test, and Kaplan-Meier analysis. RESULTS: Of 124 patients included, 74, 37, and 13 were in the OP, LNG-IUD, and combination groups, respectively. The pCR rate was 79.8% and recurrence rate was 21.2%. The pCR rates within 3 and 6 months were significantly higher in the OP group than in the LNG-IUD group, but were not significantly different within 12 and 24 months. Recurrence rate was significantly higher in the OP group than in the LNG-IUD group. The pCR rate and recurrence rate had no significant differences between the combination group and the other groups. Excluding the LNG-IUD group, 53 and 34 patients received low- and high-dose OP, respectively. The pCR and recurrence rates were comparable between the low- and high-dose OP groups. Maintenance therapy was significantly associated with lower recurrence rate. CONCLUSIONS: Although OP alone achieved more short-term pCR than the other groups, more recurrences occurred after pCR than LNG-IUD alone. High-dose OP as well as combination of OP and LNG-IUD did not increase pCR or reduce recurrence. Maintenance therapy may reduce the recurrence rate after pCR.

Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis (LILAC): a Gynecologic Oncology Research Investigators Collaboration (GORILLA-3002) retrospective study.

OBJECTIVE: This study aimed to evaluate the therapeutic role of lymphadenectomy in patients surgically treated for clinically early-stage epithelial ovarian cancer (EOC). METHODS: This retrospective, multicenter study included patients with clinically early-stage EOC based on preoperative abdominal-pelvic computed tomography or magnetic resonance imaging findings between 2007 and 2021. Oncologic outcomes and perioperative complications were compared between the lymphadenectomy and non-lymphadenectomy groups. Independent prognostic factors were determined using Cox regression analysis. Disease-free survival (DFS) was the primary outcome. Overall survival (OS) and perioperative outcomes were the secondary outcomes. RESULTS: In total, 586 patients (lymphadenectomy group, n=453 [77.3%]; non-lymphadenectomy groups, n=133 [22.7%]) were eligible. After surgical staging, upstaging was identified based on the presence of lymph node metastasis in 14 (3.1%) of 453 patients. No significant difference was found in the 5-year DFS (88.9% vs. 83.4%, p=0.203) and 5-year OS (97.2% vs. 97.7%, p=0.895) between the two groups. Using multivariable analysis, lymphadenectomy was not significantly associated with DFS or OS. However, using subgroup analysis, the lymphadenectomy group with serous histology had higher 5-year DFS rates than did the non-lymphadenectomy group (86.5% vs. 74.4%, p=0.048; adjusted hazard ratio=0.281; 95% confidence interval=0.107-0.735; p=0.010). The lymphadenectomy group had longer operating time (p<0.001), higher estimated blood loss (p<0.001), and higher perioperative complication rate (p=0.004) than did the non-lymphadenectomy group. CONCLUSION: In patients with clinically early-stage EOC with serous histology, lymphadenectomy was associated with survival benefits. Considering its potential harm, lymphadenectomy should be performed according to histologic subtype and subsequent chemotherapy in patients with clinically early-stage EOC. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0007309.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer.

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

Risk factors for the failure of first-line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3004).

OBJECTIVE: To identify the risk factors for failure of first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy in patients with advanced ovarian cancer. METHOD: Patients with stage III-IV epithelial ovarian cancer who received first-line PARPi maintenance therapy were retrospectively reviewed. Clinicopathologic factors were compared between two groups-recur/progression of disease (PD) and non-recur/PD. RESULTS: In total, 191 patients were included. Median follow-up was 9.9 months, and recurrence rate was 20.9%. BRCA mutations were found in 63.4% patients. Postoperative residual tumor (60.5% vs. 37.8%), non-high grade serous carcinoma (HGSC) (15.0% vs. 6.0%), neoadjuvant chemotherapy (NAC) (55.0% vs. 35.8%), and pre-PARPi serum CA-125 levels ≥23.5 U/mL (35.9% vs. 15.2%) were more frequently observed in the recur/PD group. Multivariate Cox-regression analysis revealed pre-PARPi serum CA-125 levels ≥23.5 U/mL (HR, 2.17; 95%CI, 1.03-4.57; p = 0.042), non-HGSC (3.28; 1.20-8.97; p = 0.021), NAC (2.11; 1.04-4.26; p = 0.037), and no BRCA mutation (2.23; 1.12-4.44; p = 0.023) as independent risk factors associated with poor progression-free survival (PFS). A subgroup analysis according to BRCA mutation status showed that pre-PARPi serum CA-125 levels ≥26.4 U/mL were the only independent risk factor for poor PFS in women with BRCA mutations (2.75; 1.03-7.39; p = 0.044). Non-HGSC (5.05; 1.80-14.18; p = 0.002) and NAC (3.36; 1.25-9.04; p = 0.016) were independent risk factors in women without BRCA mutations. CONCLUSION: High pre-PARPi serum CA-125 levels, non-HGSC histology, NAC, and no BRCA mutation might be risk factors for early failure of first-line PARPi maintenance therapy. In women with BRCA mutations, high pre-PARPi serum CA-125 levels, which represent a large tumor burden before PARPi, were the only independent risk factor for poor PFS.

Is minimally invasive radical surgery safe for patients with cervical cancer ≤2 cm in size? (MISAFE): Gynecologic Oncology Research Investigators coLLborAtion study (GORILLA-1003).

OBJECTIVE: To identify clinicopathological factors associated with disease recurrence for patients with 2018 FIGO stage IA with lymphovascular invasion to IB1 cervical cancer treated with minimally invasive surgery (MIS). METHODS: A total of 722 patients with cervical cancer between January 2010 and February 2021 were identified. Clinicopathological factors related to disease recurrence were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. To determine prognostic factors for DFS, a Cox proportional hazard regression model was used. RESULTS: Of 722 patients, 49 (6.8%) experienced disease recurrence (37 pelvis, 1 para-aortic lymph node, and 11 peritoneum). Five-year DFS and OS rates were 90.7% and 98.1%, respectively. In multivariate analysis, risk factors associated with disease recurrence were residual disease in the remaining cervix (OR, 3.122; 95% CI, 1.152-8.461; p = 0.025), intracorporeal colpotomy (OR, 3.252; 95% CI, 1.507-7.017; p = 0.003), and positive resection margin (OR, 3.078; 95% CI, 1.031-9.193; p = 0.044). The non-conization group had a higher percentage of stage IB1 (77.4% vs. 64.6%; p = 0.004) and larger tumor (10 mm vs. 7 mm; p < 0.001) than the conization group. Intracorporeal colpotomy and residual disease in the remaining cervix were independent variables associated with disease recurrence in patients undergoing MIS following conization. CONCLUSION: During MIS, patients with cervical cancer ≤2 cm in size can be vulnerable to peritoneal recurrences. Patients diagnosed with invasive cancer through conization often have low-risk pathological features, which may affect their survival outcomes.

Optimum selection criteria for secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer: A multicenter study from the Gynecologic Oncology Research Investigators coLLaborAtion group (GORILLA-3001).

BACKGROUND: To identify those most likely to benefit from secondary cytoreductive surgery (SCS), we evaluated the survival outcomes and factors predictive of prognosis in patients with recurrent ovarian cancer. METHODS: We retrospectively reviewed the medical records of patients with recurrent ovarian cancer treated at five high-volume Korean hospitals between 2010 and 2021. Recurrence characteristics, treatment methods, and potential predictors of survival were compared between the chemotherapy and surgery groups. RESULTS: Among all 670 patients, 88.1% had initial stage III/IV disease, and 215 (32.1%) underwent SCS. Among patients who underwent SCS, only those who achieved complete resection exhibited improved survival. Even in patients with residual disease < 1 cm after SCS, we observed no significant survival benefit (p = 0.942). In the multivariate Cox analysis, residual disease at primary surgery, progression-free interval, recurrence sites (≤3 regions or limited carcinomatosis), ascites, and SCS were significant predictors of survival. Meanwhile, the only factor predictive of complete resection after SCS was recurrence sites (p < 0.001). CONCLUSIONS: The benefits of SCS appear to be exclusive to cases of complete resection. We propose limited regional platinum-sensitive recurrence (≤3 regions or limited carcinomatosis) without ascites as the optimum selection criteria for SCS.

Fertility-sparing hormonal treatment in patients with stage I endometrial cancer of grade 2 without myometrial invasion and grade 1-2 with superficial myometrial invasion: Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-2001).

OBJECTIVES: To evaluate oncologic and pregnancy outcomes of fertility-sparing treatment (FST) using progestin in patients with stage I grade 2 endometrioid endometrial cancer (EC) without myometrial invasion (MI) or grade 1-2 with superficial MI. METHODS: Multicenter data of patients with stage I grade 2 EC without MI or grade 1-2 EC with superficial MI, who received FST between 2005 and 2021, were analyzed. Cox regression analysis identified independent factors for progressive disease (PD) during the FST. RESULTS: Altogether, 54 patients received FST [medroxyprogesterone acetate (500-1000 mg) in 44, megestrol acetate (40-800 mg) in 10] with concurrent levonorgestrel-releasing intrauterine devices use in 31. With median time to achieve a complete response (CR) of 10 (3-24) months, 39 patients (72.2%) achieved CR. Of the 15 patients who attempted to conceive after achieving CR, 7 (46.7%) became pregnant (2 abortions, 5 live births). During a median FST duration of 6 (3-12) months, nine patients (16.6%) were diagnosed with PD. Fifteen (38.5%) experienced recurrence with a median recurrence-free survival of 23 (3-101) months. In the multivariable analysis, tumor size before FST ≥2 cm (HR 5.456, 95% CI 1.34 to 22.14; p = 0.018) was significantly associated with a high PD rate during FST. CONCLUSION: The overall response rate to FST was promising, however, the PD rate was significant during the first 12 months of FST. Therefore, performing thorough endometrial biopsy and imaging studies is essential to strictly evaluate the extent of the disease every 3 months from FST initiation.

Feasibility of extended cycles of neoadjuvant chemotherapy in patients with advanced ovarian cancer in terms of prognosis and surgical outcomes.

OBJECTIVE: We aimed to identify the effect of an extended number of neoadjuvant chemotherapy (NAC) cycles on prognosis and surgical morbidity after interval debulking surgery (IDS) in patients with newly diagnosed advanced ovarian cancer. METHODS: Medical records of patients with advanced ovarian cancer treated with NAC and having undergone IDS were retrospectively reviewed. Clinicopathological factors were compared between two groups: conventional (≤4 cycles) and extended (≥5 cycles) NAC groups. Kaplan-Meier analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 156 patients were included, 112 patients in the conventional group and 44 patients in the extended NAC group. The extended NAC group had a significantly higher frequency of cancer antigen (CA)-125 normalization after NAC (59.1% vs. 33.9%, P = 0.004), a lower rate of bowel surgery (18.2% vs. 34.8%, P = 0.042), and a lower rate of transfusion during or after IDS (36.4% vs. 59.8%, P = 0.008) as compared to the conventional group. The complete cytoreduction rate after IDS was similar between the groups. In multivariate Cox regression analysis for PFS, radiologically stable and progressive disease after NAC (Hazard ratio [HR], 1.983; 95% Confidence interval [CI], 1.141-3.446; P = 0.015) and gross residual tumor after IDS (HR, 2.054; 95% CI, 1.414-2.983; P < 0.001) were independent risk factors for poor PFS. However, extended NAC cycles were not significantly associated with poor PFS. The median PFS was 19.5 and 16.9 months (P = 0.830), and the 5-year OS was 71.4 and 63.2% (P = 0.677) in the conventional and extended NAC groups, respectively. CONCLUSION: Our study showed that extended NAC cycles were not inferior to conventional NAC cycles in terms of survival in patients with advanced ovarian cancer and reduced surgical morbidity such as bowel surgery and transfusion during or after IDS.

Maximum daily dose of G-CSF is critical for preventing recurrence of febrile neutropenia in patients with gynecologic cancer: A case-control study.

No study has evaluated the effect of therapeutic granulocyte colony-stimulating factor (G-CSF) in preventing recurrence of febrile neutropenia (FN) and survival outcomes in gynecologic cancer patients. Objective of this study is to optimize and to identify the use of G-CSF and identify the critical factors for preventing the recurrence of FN in women undergoing chemotherapy for the treatment of gynecologic cancer. The medical records of consecutive patients who underwent chemotherapy for the treatment of gynecologic cancer and experienced FN at least once were retrospectively reviewed. Clinico-laboratory variables were compared between those with and without recurrence of FN to identify risk factors for the recurrence and the most optimal usage of G-CSF that can prevent FN. Student t test, χ2 test, and multivariate Cox regression analysis were used. A total of 157 patients who met the inclusion criteria were included. Of 157, 49 (31.2%) experienced recurrence of FN. Age ≥55 years (P = .043), previous lines of chemotherapy ≤1 (P = .002), thrombocytopenia (P = .025), total dose (P = .003), and maximum daily dose (P = .009) of G-CSF were significantly associated with recurrence of FN. Multiple regression analysis showed that age ≥55 years (HR, 2.42; 95% CI, 1.14-5.14; P = .022), previous chemotherapy ≤1 (HR, 4.01; 95% CI, 1.40-11.55; P = .010), and maximum daily dose of G-CSF ≤600 µg (HR, 5.18; 95% CI, 1.12-24.02; P = .036) were independent risk factors for recurrent FN. Multivariate Cox regression analysis showed that a maximum daily dose of G-CSF ≤600 µg was the only independent risk factor for short recurrence-free survival of FN (HR, 4.75; 95% CI, 1.15-19.56; P = .031). Dose-dense administration of G-CSF >600 µg/day could prevent recurrence of FN in women who undergo chemotherapy for the treatment of gynecologic cancer and FN. Old age and FN at early lines of chemotherapy seem to be associated with FN recurrence.

Gastrointestinal/genitourinary perforation and fistula formation with or without bevacizumab in patients with previously irradiated recurrent cervical cancer: a Korean multicenter retrospective study of the Gynecologic Oncology Research Investigators Collaboration (GORILLA) group (GORILLA-1001).

BACKGROUND: This study aims to evaluate the incidence of and identify risk factors for gastrointestinal (GI) and genitourinary (GU) fistula or perforation formation with or without bevacizumab in patients with recurrent cervical cancer who underwent pelvic radiation therapy (RT). METHODS: Medical records of patients with recurrent cervical cancer who previously underwent pelvic RT between 2007 and 2020 were retrospectively reviewed. Clinicopathological factors were compared between groups that are stratified according to: 1) fistula/perforation (+) versus (-); and 2) bevacizumab plus conventional chemotherapy (BC) versus chemotherapy alone (C). Univariate and multivariate regression analyses were performed to identify risk factors for fistula/perforation. Overall survival (OS) was compared between the different groups. RESULTS: Of 219 participants, fistula/perforation of any grade occurred in 36 patients (16.4%); 27 fistulas and 9 perforations. Bevacizumab was more frequently used in Bevacizumab was more frequently used ( +) group than fistula/perforation (-) group (p = 0.015). Multivariate analysis showed that bevacizumab administration was the only independent risk factor for fistula or perforation (HR, 3.27; 95% CI, 1.18-9.10; P = 0.023). F/P was observed more frequently in women receiving BC (n = 144) than those receiving C (n = 75) (20.8% vs. 8.0%; P = 0.019). During median follow-up of 33.7 months (1.2-185.6 months), no significant OS difference was observed between fistula/perforation ( +) vs. (-) (hazards ratio [HR], 1.78; median 84.2 months [95% CI, 59.3-109.0] vs. 129.5 months [95% CI, 114.1-144.9]; P = 0.065) or BC vs. C (HR, 1.03; median 119.8 months [95% CI, 97.3-142.3] vs. 115.7 months [95% CI, 96.0-135.4]; P = 0.928). CONCLUSIONS: This study suggests that incorporation of bevacizumab in chemotherapy regimens for treating recurrent cervical cancer in patients who underwent pelvic RT incurs considerable risk for GI/GU fistula or perforation. There were no other independent risk factors for developing GI/GU fistula or perforation in this study population.

A new quantification system for assessing the degree of acute cervical insufficiency based on physical and sonographic examination.

OBJECTIVES: Acute cervical insufficiency accounts for 10-25 % of all mid-trimester pregnancy losses. However, the definition and description for the degree of acute cervical insufficiency were obscure and different among the many studies. The aim of this study was to suggest a new 4-digit quantification system and to evaluate the outcome according to the new system in women with acute cervical insufficiency. STUDY DESIGN: A retrospective cohort study was conducted in patients with acute cervical insufficiency who underwent physical examination indicated cervical cerclage. Acute cervical insufficiency was defined as painless external os dilation with prolapsed and/or visible membranes on speculum examination. The status of fetal membranes was described using two values: 1) size of the prolapsed membrane (P, measured using ultrasound); and 2) size of visible fetal membranes (M, evaluated by speculum examination). The status of cervix was described using two values: 1) dilatation of the narrowest os (O, measured by ultrasound); and 2) functional cervical length (C, measured by ultrasound). The patients were divided into 3 groups as follows: Stage I, patients with visible fetal membranes (M > 0) but with a remaining functional cervix (C > 0) (N = 7); stage II, those with visible fetal membranes (M > 0) and a functional cervical length of 0 but without prolapsed membranes (P = 0) (N = 33); and stage III, those with prolapsed membranes (P > 0) (N = 40). RESULTS: 1) Patients who delivered before 34 weeks of gestation had a significantly lower median gestational age at cerclage operation and a significantly higher median P, M, C values than those who delivered at or beyond 34 weeks of gestation(P < 0.01 for gestational age at operation, P and M values; P < 0.05 for C value); 2) The higher the stage based on PMOC quantification system, the greater the risk of preterm delivery before <24, <32, <34, and <37 weeks of gestation (P < 0.001 for all); 3) The neonatal survival rate was 100 % (7/7) for stage I, 93.9 % (31/33) for stage II, and 60 % (24/40) for stage III. CONCLUSION: The PMOC system was a simple method to describe the individualized conditions and to predict the risk of preterm births in all spectrums of acute cervical insufficiency.

Subsequent pregnancy outcomes according to the presence of acute histologic chorioamnionitis in women with spontaneous preterm delivery.

OBJECTIVE: To compare subsequent pregnancy outcomes according to the presence of acute histologic chorioamnionitis (HCA) in women with spontaneous preterm delivery (SPTD). METHODS: Among 1,706 women who gave birth twice or more at our institution, 138 women delivered spontaneously at preterm (<37.0 weeks). Subsequent deliveries occurred at our institution and placental biopsy results were available. The study population was categorized into 2 groups based on the presence of acute HCA at the time of SPTD: HCA group (n=52) and non-HCA group (n=86). The primary outcome measures were gestational age at delivery, birthweight, and frequency of preterm delivery in subsequent pregnancies. RESULTS: The median gestational age at the time of SPTD was 34.0 weeks (interquartile range [IQR], 28.9-35.3 weeks), and the frequency of acute HCA was 52/138 (38%). There were no differences in gestational age at delivery, birthweight, and frequency of preterm delivery between the HCA group and non-HCA group (median gestational age at delivery, 38.0 weeks (IQR, 36.7-38.8 weeks) in the HCA group vs. 37.9 weeks (IQR, 35.7-39.0 weeks) in the non-HCA group; frequency of preterm delivery, 14/52 (27%) in the HCA group vs. 33/86 (38%) in the non-HCA group; and median birthweight, 3.14 kg (IQR, 2.64-3.45 kg) in the HCA group vs. 2.95 kg (IQR, 2.44-3.36 kg) in the non-HCA group; P>0.1 for all. CONCLUSION: The presence of acute HCA in women at prior SPTD did not significantly affect their subsequent pregnancy outcomes.

Uterine Arteriovenous Malformation Treated by Hysteroscopic Excision.

Uterine arteriovenous malformation (AVM) is a vascular hamartoma of the myometrium that mostly results from uterine tissue damage. Herein, we report a case of uterine AVM managed successfully by hysteroscopy. The patient had an induced abortion and subsequent persistent vaginal spotting and irregular active vaginal bleeding. Ultrasonography showed a 3.5 cm × 2.9 cm heterogeneous lesion in the endometrial cavity with increased vascularity. Symptoms were monitored without uterine artery embolization to avoid complications that may affect a future pregnancy. However, 10 days later, she presented with active vaginal bleeding. Hysteroscopic endometrial mass excision was performed. Her postoperative hemoglobin level and vital signs were stable. Biopsy of the excised mass revealed AVM. Her postoperative vaginal bleeding decreased significantly, and outpatient ultrasonography 1 month later showed no abnormal findings. This case confirms the feasibility and safety of hysteroscopic management of uterine AVMs. The hysteroscopic technique should be prioritized for managing uterine AVMs.

Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases cAMP-stimulated hepatic gluconeogenesis via inhibition of CREB.

The expression of genes encoding key hepatic gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), is regulated at the transcriptional level by a network of transcription factors and cofactors, including cAMP response element-binding protein (CREB). It has been suggested that increased endoplasmic reticulum (ER) stress in the liver impairs hepatic glucose metabolism. However, the direct effect of ER stress on hepatic gluconeogenesis is still not clear. Here, we investigated whether ER stress influences hepatic gluconeogenesis and whether this process is mediated by activating transcription factor 6 (ATF6) through the inhibition of cAMP-mediated activation of CREB. A cAMP stimulant, forskolin, and 8-bromoadenosine-cAMP increased PEPCK and G6Pase mRNA expression in H4IIE rat hepatoma cells, and ER stress induced by tunicamycin or thapsigargin decreased the expression of these genes in forskolin or 8-bromoadenosine-cAMP-treated cells. In a transient transfection study, ATF6 inhibited the PEPCK and G6Pase promoters. Also, adenovirus-mediated overexpression of ATF6 in H4IIE cells decreased forskolin-stimulated PEPCK and G6Pase gene expression. Moreover, the inhibition of endogenous ATF6 expression by small interfering RNAs restored the ER stress-induced suppression of PEPCK and G6Pase gene expression. Transient transfection of ATF6 inhibited transactivation by CREB on the PEPCK and G6Pase promoters, and a gel shift assay showed that Ad-ATF6 inhibits forskolin-stimulated CREB DNA-binding activity. Finally, we found that expression of ATF6 decreased fasting-induced PEPCK, G6Pase mRNA expression, and blood glucose levels in mice. Taken together, these data extend our understanding of ER stress and the regulation of liver gluconeogenesis by ATF6.