Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.

Cost-effectiveness analysis of hospital treatment volume and survival outcomes in endometrial cancer in Japan.

OBJECTIVE: Hospital treatment volume affects survival in patients with endometrial cancer; notably, initial treatment at high-volume centers improves survival outcomes. Our study assessed the effect of hospital treatment volume on cost-effectiveness and survival outcomes in patients with endometrial cancer in Japan. METHODS: A decision-analytic model was evaluated using the following variables and their impact on cost-effectiveness: 1) hospital treatment volume (low-, intermediate-, and high-volume centers) and 2) postoperative recurrent risk factors based on pathological findings (high- and intermediate-risk or low-risk). Data were obtained from the Japan Society of Obstetrics and Gynecology database, systematic literature searches, and the Japanese Diagnosis Procedure Combination database. Quality-adjusted life years (QALY) was used as a measure of effectiveness. The model was built from a public healthcare perspective and the impact of uncertainty was assessed using sensitivity analyses. RESULTS: A base-case analysis showed that the incremental cost-effectiveness ratio at high-volume centers was below a willingness-to-pay (WTP) threshold of ¥5,000,000 with a maximum of ¥3,777,830/4.28 QALY for the high- and intermediate-risk group, and ¥2,316,695/4.57 QALY for the low-risk group. Treatment at the high-volume centers showed better efficiency and cost-effectiveness in both strategies compared to intermediate- or low-volume centers. Sensitivity analyses showed that the model outcome was robust to changes in input values. With the WTP threshold, treatment at high-volume centers remained cost-effective in at least 73.6% and 78.2% of iterations for high- and intermediate-risk, and low-risk groups, respectively. CONCLUSION: Treatment at high-volume centers is the most cost-effective strategy for guiding treatment centralization in patients with endometrial cancer.

A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.

PURPOSE: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated. METHODS: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity. RESULTS: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response. CONCLUSION: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition. TRIAL REGISTRATION: jRCT2080222728 (January 29, 2015).

Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis.

OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.

BACKGROUND: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands. METHODS: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome. RESULTS: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs. CONCLUSION: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.