Masayuki Sekine

Human papillomavirus vaccine to prevent CIN3 or worse (CIN3+): A nationwide case–control study in Japan

AbstractAn increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age‐adjusted cohort or case–control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case–control study from April 2013 to March 2020 targeted women aged 20–26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 −OR) × 100. A total of 2790 cases and 13,990 controls (one‐to‐five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03–0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case–control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination.

Three‐year questionnaire study on human papillomavirus vaccination targeting new female college school students: Follow‐up to a 2021 report to reveal the impact of a policy change in Japan

Abstract Aim The purpose of this study was to examine the trend in human papillomavirus (HPV) vaccination rates in Japan before and after a policy change in 2022, involving resumption of active recommendation and start of catch‐up vaccination. Methods From 2021 to 2023, a web‐based questionnaire survey was administered to newly enrolled female college students in Yokohama, Japan. The questionnaire included items such as age, HPV vaccination status, HPV vaccine awareness, and awareness of catch‐up vaccination. We compared knowledge about the HPV vaccine and cervical cancer in 2021 and 2023, before and after resumption of the national vaccination program. Results The HPV vaccination rates were 5.4% in 2021, 7.5% in 2022, and 35.3% in 2023, with a significant upward trend ( p  < 0.001). A similar upward trend was observed for HPV vaccine awareness (p  < 0.001). Comparing 2022 and 2023 after the start of catch‐up vaccination, there was no significant difference in awareness of catch‐up vaccination ( p  = 0.669), but there was a significant increase in awareness of free vaccination tickets ( p  < 0.001). After resumption of the national vaccination program with adoption of the catch‐up vaccination program, there was no difference in knowledge of cervical cancer, but there was a difference in knowledge of the HPV vaccine. Conclusions Although the HPV vaccination rate has increased after the policy change, it has not recovered to the level before the suspension of active recommendation. It is important for healthcare providers and school educators to actively communicate the safety and effectiveness of the HPV vaccine.

Homologous recombination inquiry through ovarian malignancy investigations: JGOG3025 Study

AbstractThe Cancer Genome Atlas (TCGA) network has clarified that ~50% of high‐grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR‐associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next‐generation sequencing for 51 targeted genes (including 29 HR‐associated genes) in 701 ovarian cancers (298 high‐grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low‐grade serous cases, and 64 others). HRD was defined as positive when at least one HR‐associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression‐free survival (PFS) and overall survival (OS). Advanced‐stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55–0.94) and 0.57 (95% CI, 0.38–0.86) for PFS and OS, respectively, compared with those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR‐associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR‐associated gene in ovarian cancer.

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

The efficacy and safety profile of 2-weekly dosing of bevacizumab-containing chemotherapy for platinum-resistant recurrent ovarian cancer

Abstract Background Despite being widely used, to date (June 2021), the regimen of bevacizumab 10 mg/kg every 2 weeks (Q2W) combined with chemotherapy is not approved in Japan for patients with platinum-resistant recurrent ovarian cancer. In this retrospective analysis, we evaluated the usage patterns of bevacizumab administered for platinum-resistant recurrent ovarian cancer. Methods We obtained clinical data from 155 Japanese medical facilities between November 2013 and December 2018 via a survey. Items included the number of cases of platinum-resistant recurrent ovarian cancer treated with bevacizumab according to dosage. For regimens including bevacizumab 10 mg/kg Q2W, additional information was requested relating to concomitantly administered agents, and the efficacy and safety of the regimen. Results Of 1739 bevacizumab-containing regimens reported in 1633 patients with recurrent ovarian cancer, 264 used 10 mg/kg Q2W. The overall response rate (ORR) with this regimen was 26.1%. Response rates varied according to regimen and were particularly favorable when bevacizumab 10 mg/kg Q2W was administered with paclitaxel (ORR, 53.0%) versus liposomal doxorubicin (15.0%; P  < 0.0001) and irinotecan (7.7%; P  < 0.028). The most frequent Grade ≥ 3 adverse events associated with bevacizumab 10 mg/kg Q2W were neutropenia (11.7%) and hypertension (11.7%). The most frequent bevacizumab-associated Grade ≥ 3 adverse events with bevacizumab plus paclitaxel versus bevacizumab plus liposomal doxorubicin were hypertension (9.0% versus 13.9%) and proteinuria (3.0% versus 8.4%). Conclusions Bevacizumab 10 mg/kg Q2W appears efficacious for patients with recurrent ovarian cancer, with a manageable toxicity profile. Approval of this regimen is clinically desirable for Japanese patients with ovarian cancer.

Precision medicine for hereditary tumors in gynecologic malignancies

AbstractGenomic medicine for gynecologic tumors is characterized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Poly ADP‐ribose polymerase (PARP) inhibitor, olaparib, and the immune checkpoint inhibitor, pembrolizumab, which are drugs that show sensitivity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clinical use, platinum sensitivity is used as a clinical surrogate marker for olaparib sensitivity, and microsatellite instability is used as a biological surrogate marker for pembrolizumab sensitivity. BRCA genetic testing and microsatellite instability test have been used as companion diagnostics before starting olaparib and pembrolizumab treatment, respectively. Homologous recombination deficiency test could be used for companion diagnostic of olaparib combination with bevacizumab in first‐line maintenance treatment and niraparib without re‐administration of platinum agents in the treatment of recurrence. The approval of the three drugs has been changing the treatment of gynecologic malignancies. Furthermore, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with germline BRCA1/2 mutation in Japan. This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.

Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy

We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received The average age at diagnosis of OC in g There appears to be no difference in the age at diagnosis of OC depending on the type of

Effectiveness of human papillomavirus vaccine against cervical precancer in Japan: Multivariate analyses adjusted for sexual activity

AbstractJapanese girls aged 12–16 years are offered free human papillomavirus (HPV) vaccination and cervical cancer screening is conducted with cytology and not HPV testing from the age of 20 years. So far, no study has analyzed the effect of HPV vaccination against cervical precancers considering HPV infection status and sexual activity. We aimed to analyze the vaccine effectiveness (VE) against HPV infection and cytological abnormalities, adjusted for sexual activity. This study comprised women aged 20–26 years who underwent cervical screening in Niigata. We obtained HPV vaccination status from municipal records and a questionnaire along with information concerning sexual activity. Of 5194 women registered for this study, final analyses included 3167 women in the vaccinated group (2821 vaccinated women prior to sexual debut) and 1386 women in the unvaccinated group. HPV 16/18 (0.2% vs 3.5%), 31/45/52 (3.4% vs 6.6%), and 31/33/45/52/58 (5.0% vs 9.3%) positive rates were significantly lower in the vaccinated group (P < 0.001). No women vaccinated before sexual debut had HPV 16/18‐related cytological abnormalities. VE for HPV 16/18 infection and high‐grade cytological abnormalities in women vaccinated prior to sexual debut were 95.8% (95% CI 81.9–99.0%; P < 0.001) and 78.3% (95% CI 11.3–94.7%; P = 0.033), respectively, in multivariate analyses adjusted for age and number of sexual partners. However, analyses of all vaccinated women did not show significant effectiveness against cytological abnormalities. Our results showed the effectiveness of HPV vaccine against high‐grade cervical cytological abnormalities and the importance of the vaccination before sexual debut.

The Effect of a Web-Based Cervical Cancer Survivor’s Story on Parents' Behavior and Willingness to Consider Human Papillomavirus Vaccination for Daughters: Randomized Controlled Trial

Background Providing adequate information to parents who have children eligible for human papillomavirus (HPV) vaccination is essential to overcoming vaccine hesitancy in Japan, where the government recommendation has been suspended. However, prior trials assessing the effect of brief educational tools have shown only limited effects on increasing the willingness of parents to vaccinate their daughters. Objective The aim of this trial is to assess the effect of a cervical cancer survivor’s story on the willingness of parents to get HPV vaccination for their daughters. Methods In this double-blinded, randomized controlled trial (RCT) implemented online, we enrolled 2175 participants aged 30-59 years in March 2020 via a webpage and provided them with a questionnaire related to the following aspects: awareness regarding HPV infection and HPV vaccination, and willingness for HPV vaccination. Participants were randomly assigned (1:1) to see a short film on a cervical cancer survivor or nothing, stratified by sex (male vs female) and willingness for HPV vaccination prior to randomization (yes vs no). The primary endpoint was the rate of parents who agreed for HPV vaccination for their daughters. The secondary endpoint was the rate of parents who agreed for HPV vaccination for their daughters and the HPV vaccination rate at 3 months. The risk ratio (RR) was used to assess the interventional effect. Results Of 2175 participants, 1266 (58.2%) were men and 909 (41.8%) were women. A total of 191 (8.8%) participants were willing to consider HPV vaccination prior to randomization. Only 339 (15.6%) participants were aware of the benefits of HPV vaccination. In contrast, 562 (25.8%) participants were aware of the adverse events of HPV vaccination. Although only 476 (21.9%) of the respondents displayed a willingness to vaccinate their daughters for HPV, there were 7.5% more respondents in the intervention group with this willingness immediately after watching the short film (RR 1.41, 95% CI 1.20-1.66). In a subanalysis, the willingness in males to vaccinate daughters was significantly higher in the intervention group (RR 1.50, 95% CI 1.25-1.81); however, such a difference was not observed among females (RR 1.21, 95% CI 0.88-1.66). In the follow-up survey at 3 months, 1807 (83.1%) participants responded. Of these, 149 (8.2%) responded that they had had their daughters receive vaccination during the 3 months, even though we could not see the effect of the intervention: 77 (7.9%) in the intervention group and 72 (8.7%) in the control group. Conclusions A cervical cancer survivor’s story increases immediate willingness to consider HPV vaccination, but the effect does not last for 3 months. Furthermore, this narrative approach to parents does not increase vaccination rates in children eligible for HPV vaccination. Trial Registration UMIN Clinical Trials Registry UMIN000039273; https://tinyurl.com/bdzjp4yf

Long‐term effectiveness of HPV vaccination against HPV infection in young Japanese women: Real‐world data

AbstractIn Japan, public funding for HPV vaccination began in 2010 for girls aged 13–16 years (birth cohort years 1994–1997) and women born in 1994 who turned 25 in 2019. We aimed to verify the long‐term effectiveness of the bivalent HPV vaccine in women aged 25 years. Subjects were women aged 25–26 years who underwent cervical cancer screening and HPV testing in Niigata from 2019 to 2020 (birth cohort years 1993–1994). Information on vaccination status and sexual behavior was obtained from a questionnaire and municipal records. We compared the HPV infection rates of the vaccinated and unvaccinated groups. Of the 429 registrants, 150 (35.0%) and 279 (65.0%) were vaccinated and unvaccinated, respectively. The average period from HPV vaccination to HPV testing was 102.7 months (8.6 years), with a median of 103 months (range 92–109 months). The HPV high‐risk infection rate was 21.3% (32/150) in the vaccinated group and 23.7% (66/279) in the unvaccinated group (P = 0.63). The HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (P = 0.0018), and the vaccine effectiveness was 100%. The cross‐protective type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%, P = 0.013). There was no significant difference in the mean age at sexual debut and the number of previous sexual partners between the two groups. We have demonstrated the long‐term 9‐year effectiveness of the bivalent vaccine against HPV infection for the first time in Japan.