Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis.

AIM: Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS: We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS: Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS: The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.

A survey of carboplatin desensitization therapy in Japan: A multicenter retrospective study.

INTRODUCTION: Hypersensitivity reactions (HSRs) to chemotherapy are serious adverse events associated with cancer drug therapy and can occur with any antitumor drug. This study investigated the safety and efficacy of carboplatin desensitization therapy in Japan and established a method for treating carboplatin HSRs. METHODS: Patients diagnosed with gynecological (ovarian, endometrial, or cervical) cancers who underwent carboplatin desensitization therapy between 2016 and 2020 at the Gynecologic Cancer Study Group of Japan Clinical Oncology Group were included. The carboplatin desensitization therapy at each institution and the implementation cases were registered in an online case report form. RESULTS: This retrospective study enrolled 136 patients (ovarian, 108; endometrial, 17; and cervical cancer, 11). Pre-existing allergies were present in 37 (27.2%) patients, and 32 (23.5%) patients exhibited prodromal symptoms during treatment before HSR onset. Erythema was the most common symptom at HSR onset, affecting 93 (68.4%) patients, followed by itching in 72 (52.9%) patients and decreased oxygen saturation in 43 (31.6%) patients. Loss of consciousness occurred in three (2.2%) patients. The most common timing of HSR onset was during the first recurrence treatment (47%). The mean total carboplatin dose until HSR onset was 7331 (2620-18,282) mg, and the mean number of doses was 14 (4-63). Desensitization treatment was completed in 75% of cases, and breakthrough HSRs occurred in 25% (34/136). No deaths occurred in the study cohort. The risk factors for HSRs were not identified. CONCLUSION: Although carboplatin desensitization therapy has high success rates in Japan, erythema and pruritus are important HSRs to consider.

Analysis of East Asia subgroup in Study 309/KEYNOTE-775: lenvatinib plus pembrolizumab versus treatment of physician's choice chemotherapy in patients with previously treated advanced or recurrent endometrial cancer.

OBJECTIVE: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. METHODS: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. RESULTS: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. CONCLUSION: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03517449.

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).

Cerebral infarction caused by Trousseau syndrome associated with cervical cancer.

OBJECTIVE: The combination of cancer and hypercoagulable states is often called Trousseau syndrome. In particular, cerebral infarction caused by Trousseau syndrome is reported to have a poor prognosis. In gynecology, there are many reports of ovarian cancer and a few of uterine cancer. Since there has been no comprehensive report of Trousseau syndrome in cervical cancer, we aimed to summarize Trousseau syndrome in cervical cancer. METHODS: Cerebral infarction caused by cancer-related arterial thrombosis was defined as Trousseau syndrome. Patients with cervical cancer diagnosed at our hospital between January 2014 and December 2021 were retrospectively reviewed using the hospital's medical records. RESULTS: A total of 1,432 patients were included in the study. Trousseau syndrome occurred in 6 patients (0.4%). The mean age of patients with Trousseau syndrome was 63 years (range: 53-78 years). Of the 6 patients who developed Trousseau's syndrome, 4 patients had it before or during initial treatment, and 2 during recurrent/relapsed disease treatment. The 4 patients who developed the syndrome before or during initial treatment had advanced disease: 1 in stage IIIC and 3 in stage IVB. In all cases, the disease was associated with progressive distant metastasis. The median survival time from the onset of Trousseau syndrome was 1 month (range: 0-6 months). CONCLUSION: Cervical cancer causes Trousseau syndrome in cases of advanced disease with a short time between the onset of the syndrome and mortality.

Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial.

BACKGROUND: The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. METHODS: In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing. FINDINGS: Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. INTERPRETATION: Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. FUNDING: F Hoffmann-La Roche.

Risk-reducing decisions regarding germline BRCA pathogenic variant: focusing on the timing of genetic testing and RRSO.

BACKGROUND: In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan. METHODS: This retrospective analysis included 350 women with germline BRCA (gBRCA) pathogenic variants (PVs) who had visited gynaecologists; they received gBRCA genetic testing at 45.1±10.6 (20-74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher's exact tests. RESULTS: The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with gBRCA-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO. CONCLUSION: Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.

Local Treatment Efficacy for Single-Area Squamous Cell Carcinoma of the Unknown Primary Site.

The prognosis for cancer of unknown primary site (CUP) is poor, and squamous cell carcinoma of the unknown primary site (SCCUP) is a rare histological type. CUP is often treated with aggressive multimodal treatments, while the treatment of single-area localized CUP remains controversial. We retrospectively reviewed the medical records of patients with CUP. SCCUP in women was classified according to several definitions. Based on the histologic type and site, they were classified into favorable and unfavorable subsets. We further divided SCCUP into two types (single and multiple areas) and reviewed treatment and efficacy. Among the 227 female CUP patients, 36 (15%) had SCCUP. The median age was 59.9 years (range, 31-90 years). Most patients (61.1%) had a good performance status. Of the SCCUP patients, 22 had cancer in a single area, and 14 in multiple areas. Single-area SCCUP was further divided into favorable (16 cases) and unfavorable subsets (6 cases). In the favorable subset, local treatment was predominant, and almost all cases had a good prognosis. Even in the unfavorable subset, local therapy was combined with systemic chemotherapy in only two cases, and four cases showed no recurrences. Local treatment may be effective for single-area SCCUP, even in the unfavorable subset.

Serum Creatinine Elevation as a Risk Factor for Niraparib-induced Hematologic Toxicity.

BACKGROUND/AIM: Niraparib dosages can be individualized to reduce the starting dose based on body weight and baseline platelet count. However, even with individualized dosing, scattered cases of ≥Grade 3 hematologic toxicity occur. This study explored markers predictive of serious hematologic toxicity in niraparib therapy. PATIENTS AND METHODS: This retrospective observational study investigated patients who started niraparib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between December 2020 and March 2022. Associations between hematologic toxicities and serum creatinine ratio (percentage increase in serum creatinine between baseline and after niraparib initiation) were investigated. RESULTS: Out of 50 ovarian cancer patients who initiated niraparib, 45 patients were included in the final analysis. Twenty-three patients (51.1%) developed ≥Grade 3 hematologic toxicity, with neutropenia in 17 (37.8%), anemia in 9 (20.0%), and thrombocytopenia in 4 (8.9%). Patients with Grade 4 hematologic toxicity showed higher serum creatinine ratios than those with ≤Grade 2. Thrombocytopenia ≥Grade 3 occurred only within 2 months of niraparib initiation and was preceded by an increase in serum creatinine in all affected patients. CONCLUSION: Serum creatinine ratio offers a potential marker for predicting severe hematologic toxicity following niraparib therapy.

Retrospective study of the efficacy and safety of docetaxel/carboplatin combination therapy as postoperative adjuvant chemotherapy for nonsquamous cell carcinoma of the cervix.

OBJECTIVE: Optimal adjuvant chemotherapy for nonsquamous cervical carcinoma has not yet been established. This study investigated the efficacy and safety of docetaxel/carboplatin (DC) for early-stage nonsquamous cell cervical carcinoma after radical hysterectomy (RH). METHODS: We evaluated 157 patients with stage IB-IIB nonsquamous cervical carcinoma with intermediate risk and high risk treated at our institution with DC after type II or III RH from 2007 to 2021. Patients received docetaxel (60-70 mg/m2) and carboplatin (area under the curve 5-6) every 3 weeks for six cycles. The primary endpoint was 2 year recurrence-free survival (RFS) and the secondary endpoint was adverse events (AEs). RESULTS: There were 106 intermediate-risk and 51 high-risk patients. The high-risk patients included 11 with positive parametrial involvement, 20 with pelvic lymph node metastases, and 20 with both parametrial involvement and pelvic lymph node metastases. The 2 year RFS rates for intermediate-risk, high-risk, and positive pelvic lymph nodes were 94.8% (95% confidence interval [CI], 87.9-97.8), 80.1% (95% CI, 64.1-89.5), and 74.5% (95% CI, 55.4-86.4), respectively. Sixteen patients had recurrence, including local recurrence (n = 6), distant metastasis (n = 9), and local and distant metastasis (n = 1). Hematologic toxicity was the most frequent AE, especially leukopenia and neutropenia. Nausea and constipation were the most frequent nonhematologic toxicities. CONCLUSION: DC therapy at our institution showed good 2 year RFS, and postoperative adjuvant therapy with DC therapy is suggested as a useful strategy for patients with nonsquamous cervical carcinoma.

Efficacy of intra-abdominal cytoreductive surgery in advanced endometrial cancer with distant metastasis.

OBJECTIVE: The efficacy of intra-abdominal cytoreductive surgery in patients with endometrial cancer and distant metastasis is equivocal. We investigated the effectiveness of such surgical treatment and whether it should be performed before or after chemotherapy (CT). METHODS: This study included patients with an International Federation of Gynecology and Obstetrics stage IVB endometrial cancer who received initial treatment at our hospital between January 2006 and December 2017. RESULTS: We retrospectively reviewed 67 patients with stage IVB endometrial cancer with distant metastases and classified them into preceding surgery (PS, n=23), chemotherapy followed by a surgery (CS, n=27), and CT (n=17) groups. We examined the achievement of resection with [R (1)] or without [R (0)] intra-abdominal macroscopic residue and survival. The median survival time for R (0) was 44 (95% confidence interval [CI]=9-not available [NA]) months in the PS group and 27 (95% CI=11-NA) months in the CS group. The median survival time for R (1) was 9 (95% CI=0-24) months in the PS group and 12 (95% CI=7-19) months in the CS group. The similar prognosis in both groups was worse with R (1) than with R (0). The survival curve for R (1) in the resection groups was similar to that of the CT group. CONCLUSION: Achieving resection without intra-abdominal macroscopic residue for endometrial cancer with distant metastases, whether before or after CT, could extend patients' survival.

Comparison of Paclitaxel plus Carboplatin versus Observation in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck.

INTRODUCTION: Although systemic therapy, including multi-kinase inhibitors and cytotoxic chemotherapy, is an option for recurrent or metastatic adenoid cystic carcinoma of the head and neck (HNACC), it is not proven whether these therapies can prolong overall survival (OS). The present study investigated the impact of cytotoxic chemotherapy on survival outcomes compared with observation without chemotherapy. METHODS: We retrospectively reviewed the medical records of the patients diagnosed with recurrent or metastatic HNACC. We compared the survival outcomes, including survival time from recurrence/metastasis (OS) patients who received systemic chemotherapy with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6) (TC) on day 1 of a 3-week cycle and observation alone. Subgroup analysis was conducted to identify patients who can get benefit from TC. RESULTS: Seventy-five patients (32 in TC and 43 in observation) were analyzed. There was no difference in median OS between TC and observation (52.2 months vs. 44.0 months, hazard ratio 0.76, 95% confidence interval 0.32-1.30, p = 0.21). Landmark analysis to reduce immortal bias also showed no difference between TC and observation in terms of OS. Subgroup analysis showed nonsignificant trends toward longer OS in asymptomatic patients with pulmonary metastasis and without bone metastasis. CONCLUSIONS: In our non-randomized comparison, patients who underwent TC did not show prolonged survival time from recurrence and/or metastasis diagnosis compared with observation alone in patients with recurrent or metastatic HNACC. Although systemic chemotherapy is a possible option for metastatic/recurrent HNACC, initial observation might be a valid strategy for asymptomatic patients without extrapulmonary diseases. Further research is warranted to identify the optimal patients and therapeutic regimens to prolong OS in HNACC.

Clinical characteristics of sarcoma cases in which long-term disease control was achieved with trabectedin treatment: A retrospective study.

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin.

Impact of the coverage of risk-reducing salpingo-oophorectomy by the national insurance system for women with BRCA pathogenic variants in Japan.

To determine the impact of the coverage of risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) as well as genetic testing for BRCA pathogenic variants by the national insurance system in Japan. We compared the clinical background of women who underwent RRSO at our institution before and after its coverage by the national insurance system. Those who underwent RRSO between January 2017 and December 2019 and between April 2020 and March 2022 were classified as Period. A and B, respectively. Overall, 134 women underwent RRSO during the study period. In Period A and B, 45 and 89 women underwent RRSO for the study period was 36 and 24 months, respectively. Compared with Period A, the number of women who underwent RRSO per month increased by threefold in Period B (p < 0.01). In addition, the number of women who underwent surgery for breast cancer along with RRSO increased in Period B (p < 0.01). Although the number of women who underwent concurrent RRM with RRSO in Period B increased, the difference was not statistically significant. Compared with Period A, the number of women diagnosed with BRCA pathogenic variant increased by 3.9-fold, and the proportion of women who underwent concurrent hysterectomy at the time of RRSO decreased from 66 to 7.9% in Period B (p < 0.01). Owing to the introduction of the national insurance system, the number of women who underwent RRSO and concurrent surgery for breast cancer at the time of RRSO increased in Japan.

Implementation of microsatellite instability testing for the assessment of solid tumors in clinical practice.

BACKGROUND: In Japan, microsatellite instability (MSI) testing for solid tumors was introduced in clinical practice in December 2018. Although immune checkpoint inhibitors (ICIs) are established standards of care for patients with MSI-high tumors, the status of implementing MSI testing in clinical practice remains unclear. METHODS: We retrospectively reviewed the medical records of patients with solid tumors who underwent MSI testing between January 2019 and December 2020 at our institution. RESULTS: In total, 1,052 MSI tests were performed in 1,047 patients. Regardless of specimen volume and condition, the MSI status was successfully determined in 1,041 (99.0%) tests, encompassing 27 tumor types (microsatellite stable [MSS] or MSI-low: n = 991 [95.2%] and MSI-high: n = 50 [4.8%]). Patients whose specimens were fixed with 20% neutral buffered formalin (NBF) and who had specimens with prolonged storage (98.4% and 95.4%) showed lower success rates than those whose specimens were fixed with 10% NBF and who had specimens with nonprolonged storage (100.0% and 99.6%), respectively. The prolonged turnaround time (TAT) in MSI-high cases (median TAT: 24 days) was a critical issue that directly resulted in treatment delay. Of the 50 patients with MSI-high tumors, 24 (48.0%) received ICIs and 34 (68.0%) were referred to the Department of Clinical Genetic Oncology where 6 (12.0%) patients were diagnosed with Lynch syndrome. CONCLUSIONS: MSI testing was successfully performed for various types of tumors and specimens in clinical practice. Our study results identified certain issues associated with the clinical implementation of MSI testing, including optimal specimen selection, extended TAT in MSI-high cases, and awareness of hereditary tumors.

Druggable gene alterations in Japanese patients with rare malignancy.

Without a current standard of care, patients with rare malignancy are subjected to precision oncology with next-generation sequencing to identify a course of treatment. We sought to establish the clinical relevance of comprehensive genomic profiling (CGP) among patients with rare malignancy. Rare malignancy was defined using the Rare Cancers in Europe definition (<6 cases per 100,000 individuals). We analyzed gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Level A gene alterations, categorized using Clinical Interpretations of Variants in Cancer and MD Anderson Knowledge Base for Precision Oncology, were considered druggable. Rare malignancy accounted for 149 (45%) cases, with female genital cancers (32%) most common. Among the rare malignancy cases, we identified a lower frequency of mutation in TP53 (41% vs. 60%, P<0.001), KRAS (13% vs. 43%, P<0.001) and APC (3% vs. 25%, P<0.001), and a higher frequency of ARID1A mutation (14% vs. 6%, P=0.03), as compared with common malignancies. TMB-high and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 37 patients with rare malignancy; this percentage tended to be higher than that for patients with common malignancies (25% vs. 17%, P=0.08). Common druggable alterations were BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variant. Five of the 37 patients with druggable alterations received genome-driven treatment. There was no significant difference in overall survival between the rare and common malignancy groups. Our results provide clues for future clinical development and treatment success among Japanese patients with rare cancers.

Detection of BRCA1 Pathogenic Variant in a 24-Year-Old Endometrial Cancer Patient: Risks of Several Hereditary Tumor Syndromes Assessed Using Germline Multigene Panel Testing.

A 24-year-old woman suspected of Lynch syndrome was found to carry a BRCA1 pathogenic variant, based on germline multigene panel testing (MGPT). The patient was diagnosed with endometrial carcinoma and underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and omentectomy at the age of 23. Based on her father's history of colorectal cancer and her history of early onset endometrial cancer, mismatch repair protein immunohistochemistry analysis was performed. However, no loss of expression for mismatch repair proteins was found. Given her family history of ovarian and breast cancers, MGPT was recommended to identify the presence of any hereditary tumor syndromes. This testing revealed a BRCA1 pathogenic variant (exon13: c.1016delA, p.Lys339ArgfsX2) and diagnosed as hereditary breast and ovarian cancer syndrome (HBOC). Subsequently, the patient's mother also underwent single-site analysis for this variant, and the same pathogenic variant was detected. The patient and her mother are at high risk of developing BRCA1-associated HBOC-related cancers. Based on family history, clinical surveillance is currently underway for this patient and her mother. Currently, MGPT offers the potential for comprehensive genetic cancer risk assessment and may provide a more rational approach for the genetic assessment of those individuals whose personal and family cancer histories do not fit neatly into a single syndrome. This case suggests that if a patient is at high risk for hereditary tumor syndromes, MGPT should be considered to improve disease management strategies in clinical settings.

Impact on prognosis of unexpected uterine sarcoma with scalpel morcellation or enucleation.

Objective: It is well known that power morcellation of unexpected uterine sarcoma affects prognosis. There are few reports on the effects of scalpel morcellation or myomectomy of uterine sarcoma on prognosis, which is not well understood. This study investigated the effect on recurrence and prognosis when tumors of uterine sarcoma undergo scalpel morcellation or myomectomy. Methods: We performed a retrospective, observational study by collecting data from the medical records of patients who were histologically diagnosed with uterine sarcoma at our hospital between 2005 and 2017. All patients with unexpected uterine sarcoma were diagnosed after laparoscopic hysterectomy with scalpel morcellation or myomectomy (abdominal and laparoscopic) for presumed myoma. We evaluated recurrence rate, recurrence site, progression-free survival (PFS), and overall survival (OS). Results: A total of 15 patients were examined in this study. Twelve patients underwent myomectomy (7 patients with open surgery, 5 patients with laparoscopic surgery), and 3 patients underwent total laparoscopic hysterectomy with transvaginal scalpel morcellation. There were 11 cases of recurrence, and the recurrence rate was 78 %. The recurrence site was peritoneal dissemination in 10 cases (91 %) and lymph node metastasis in 1 case (9 %). The median PFS was 32 months [95 % confidence interval (CI) = 6.5-NA], and the median OS was 95.5 months [95 % CI = 55.8-NA]. Conclusion: Power morcellation, scalpel morcellation, and myomectomy may affect recurrence and prognosis. Further studies are needed in the future.

Pembrolizumab plus chemotherapy in Japanese patients with persistent, recurrent or metastatic cervical cancer: Results from KEYNOTE-826.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.