Ovarian cancer

Development of a novel specific biomarker, tissue factor pathway inhibitor 2, for preoperative prediction of clear cell carcinoma of the ovary

Author(s)：: Etsuko Miyagi¹, Noriyuki Arakawa², Kentaro Sakamaki³, Naho Ruiz Yokota¹, Yuki Yamada⁴, Satoshi Yamaguchi⁵,
Shoji Nagao⁵, Yasuyuki Hirashima⁶, Yuka Kasamatsu⁶, Hisamori Kato⁷, Tae Mogami⁸, Yohei Miyagi⁹, Kobayashi Hiroshi⁴
Affiliation(s)：: ¹Department of Obstetrics and Gynecology, Hospital, Yokohama City University, ²Division of Medical Safety Science, National Institute of Health Scinences,³Center for Data Science,, Yokohama City University,⁴Department of Obstetrics and Gynecology, Medical Faculty Medical department, Nara Medical University,⁵Department of Gynecologic Oncology, Hyogo Cancer Center,⁶Division of Gynecology, Shizuoka Cancer Center,⁷Division of Gynecology, Kanagawa Cancer Center,⁸Department of Gynecology, Medical center, Yokohama City University,⁹Research Institute, Kanagawa Cancer Center

Background: Clear cell carcinoma (CCC) of the ovary is an endometriosis-associated epithelial ovarian cancers (EOCs) and often exhibits resistance against standard chemotherapies. We identified Tissue Factor Pathway Inhibitor 2 (TFPI2) in media conditioned by CCC-derived cell lines using a modified proteomics technique, and found that TFPI2 is a candidate of novel serum biomarkers that discriminates CCCs from borderline ovarian tumors (BOTs) and non-clear EOCs. Next, we developed a highly efficient automated enzyme-linked immunosorbent assay system for TFPI2 detection, and examined the performance of TFPI2 for preoperative diagnosis of CCCs.
Methods: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCCs from BOTs, other EOCs, and benign lesions were compared.
Results: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%) with the defined cutoff level. In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCCs from BOTs and other EOCs was improved from 43.5% to 71.0% when combined with CA125.
Conclusions: High specificity of TFPI2 for preoperative detection of CCCs was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 will contribute substantially to precise prediction of CCC in clinical practice.

Neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian cancer in Japan. GOTIC-019: a multi-institutional retrospective cohort study.

Author(s)：: Shoji Nagao¹, Jun Tamura², Takashi Shibutani¹, Maiko Miwa³, Tomoyasu Kato⁴, Toyomi Satoh⁵, Yuji Takei⁶, Natsuko Kamitani⁷, Naoki Inoue⁸, Kazuto Nakamura⁹, Aya Inoue¹⁰, Keiichi Fujiwara³, Mitsuaki Suzuki¹¹
Affiliation(s)：: ¹Gynecologic Oncology, Hyogo Cancer Center, ²Biostatistics, School of Medicine, Yokohama City University,³Gynecologic Oncology, International Medical Center, Saitama Medical University,⁴Gynecologic Oncology, National Cancer Center Hospital,⁵Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba,⁶Obstetrics and Gynecology, School of Medicine, Jichi Medical University,⁷Obstetrics and Gynecology, School of Medicine, Yokohama City University,⁸Obstetrics and Gynecology, Faculty of Medicine, Gunma University,⁹Gynecologic Oncology, Gunma Prefectural Cancer Center,¹⁰Obstetrics and Gynecology, School of Medicine, Ehime University,¹¹Obstetrics and Gynecology, Shin-Yurigaoka General Hospital

Background: Since several randomized controlled trials have demonstrated that neoadjuvant chemotherapy (NAC) was non-inferior to primary debulking surgery (PDS) with respect to survival in advanced ovarian cancer, many patients are now treated with NAC followed by interval debulking surgery (IDS). We examined the actual status and effectiveness of treatment strategy using NAC followed by IDS in Japanese clinical practice.
Methods: We conducted a multi-institutional observational study of 940 women with FIGO stage III to IV epithelial ovarian cancer treated at 9 centers from 2010 to 2015. In 486 propensity-score matched samples extracted from the participants, progression-free survival (PFS) and overall survival (OS) were compared between NAC and PDS.
Results: The adoption of NAC varied by institution from 21 to 67%, and overall 512 patients (54.5%) received NAC. NAC was tended to have shorter OS [median OS: 48.1 vs. 68.2 months, hazard ratio (HR): 1.34; 95% confident interval (CI): 0.99-1.82, p =0.06], but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80-1.31, p =0.88) in FIGO stage IIIC. On the other hand, NAC and PDS were comparable in PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74-1.53, p =0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65-1.47, p =0.93) among patients with FIGO stage IV. Median PFS in patients with complete, optimal (macroscopic residual tumor <1cm), suboptimal surgery at IDS or PDS were 21.5, 16.8, 17.7, and 43.1, 18.6, 14.3 months, median OS were 57.2, 46.0, 42.2, and not reached, 68.2, 34.6 months, respectively.
Conclusions: More than half of the patients with advanced ovarian cancer received NAC. However, NAC did not improve survival in these patients, particularly, it may be associated with shorter OS in patients with FIGO stage IIIC.

Prognostic aspects of positive ascites cytology and effects of therapeutic interventions in epithelial ovarian cancer: a large-scale multi-institutional study

Author(s)：: Masato Yoshihara¹, Kazuhisa Kitami¹, Kazumasa Mogi¹, Kaname Uno¹, Shohei Iyoshi¹, Nobuhisa Yoshikawa¹, Hiroaki Kajiyama¹
Affiliation(s)：: ¹Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University

Positive ascites cytology is a strong prognostic factor in patients with ovarian cancer (OvCa) confined to the ovary. However, limited information is currently available on the impact of positive ascites cytology on patient prognoses under each clinical background and stage or the effectiveness of additional therapeutic interventions, including complete staging surgery and chemotherapy. We herein investigated the comprehensive impact of positive ascites cytology on patients with epithelial OvCa and the effectiveness of additional therapeutic interventions, including complete staging surgery and chemotherapy. A multicenter retrospective study between 1986 and 2019 was conducted. Among 4,730 patients with malignant ovarian neoplasms, 1,906 with epithelial OvCa were included. In the investigation of its effects on clinical factors using a multivariate analysis, positive ascitic cytology correlated with a poor prognosis [hazard ratio (HR) of progression-free survival (PFS), 1.541, 95% confidence interval (CI), 1.300-1.827, P <0.001; HR of overall survival (OS), 1.666, 95% CI, 1.359-2.041, P <0.001]. In most subgroups, patients with positive ascites cytology had a significantly worse prognosis than those with negative cytology. The results of ascites cytology did not significantly affect the prognosis of patients with stage IV tumors and a mucinous histology. Chemotherapy may be effective in reducing the negative impact of positive ascites cytology on the prognosis of patients in terms of PFS and OS. In comparison, complete staging surgery did not improve the prognosis of patients with positive ascites cytology. Collectively, our findings suggested that positive ascites cytology had a negative impact on the prognosis of patients with epithelial OvCa, but not those with stage IV tumors or a mucinous histology.

Attitude and behavior of gynecologic oncologists to subsequent primary cancer prevention of gynecologic cancer survivors: the JGOG questionnaire survey

Author(s)：: Mikiko Sato¹, Nao Suzuki², Hitomi Sakai³, Yoshio Itani⁴, Shinya Sato⁵, Masayuki Futagami⁶, Yoshio Yoshida⁷
Affiliation(s)：: ¹Department of Obstetrics and Gynecology, School of Medicine Itabashi Hospital, Nihon University, ²Department of Obstetrics and Gynecology, St.Marianna University,³Advanced Cancer Translational Research Institute, Showa University,⁴Palliative Care Cente, Yao Municipal Hosptal,⁵Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University,⁶Department of Obstetrics and Gynecology, Graduate of Medicine, Hirosaki University,⁷Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui

[Aim] Subsequent primary cancer (SPC) prevention is becoming an essential issue for cancer survivors. However, the appropriate manner or organized system for SPC prevention has not been established. Therefore, this study aimed to seek the attitude and behavior of gynecologic oncologists to SPC prevention to get the clue for developing the SPC prevention system in Japan.
[Method] We conducted a web-based questionnaire survey about various issues of gynecologic cancer survivors for the Japan Gynecologic Oncology Group (JGOG) members. In this study, we analyzed the answers to the questions about SPC prevention among a total of 83 queries.
[Results] We received 313 responses. The mean number of years of experience as a doctor was 22.05 years, 72.8% were male, and 81.0% worked at a Ministry of Health, Labour and Work-designated cancer hospital. Sixty percent of the participants proactively recommend to receive SPC screening to their patients, and 44.4% consider that SPC prevention is the responsibility of gynecologic oncologists. On the other hand, 82.1% answered that they guide SPC prevention verbally, and 31.0% do not tell the survivors the appropriate place to receive SPC screening. The main barriers to educate SPC prevention were lack of time to talk during an outpatient clinic (36.7%) and lack of guidelines or information to instruct the patients (11.5%).
[Conclusion] Japanese gynecologic oncologists possess high awareness of SPC prevention issues. On the other hand, there is a concern that lack of information about appropriate SPC prevention makes the guidance by gynecologic oncologists complacent. Moreover, the gynecologic oncologists' claim that the lack of time for this issue during their practice suggests a benefit of a multi-disciplinary support system for cancer survivor health care.