Shiro Suzuki

Real‐world data of poly (ADP‐ribose) polymerase inhibitor response in Japanese patients with ovarian cancer

AbstractBackgroundPoly (ADP‐ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored.MethodsThis retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined.ResultsHigh‐grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high‐grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non‐responders. Furthermore, neutrophil counts were significantly higher among responders than among non‐responders.ConclusionsInflammation‐related blood data, such as neutrophil count, obtained at the initial pre‐treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma

The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. The median follow-up duration of all surviving women was 52.8 (1.6-184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633-2.187; p=0.615). This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan-Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4-6 cycles of taxane plus platinum adjuvant chemotherapy. Eighty-nine and 138 patients received ≤ 3 and 4-6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4-6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518-2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619-2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

Paclitaxel‐carboplatin plus bevacizumab therapy for advanced neuroendocrine carcinoma of the uterine cervix: A retrospective case series

AbstractAimThere is no conclusive data on the prognosis of patients who receive paclitaxel‐carboplatin (TC) plus bevacizumab therapy for advanced neuroendocrine carcinoma (NEC) of the uterine cervix, a rare histological subtype of cervical cancer. Thus, the aim of this study was to determine the efficacy of TC chemotherapy plus bevacizumab and bevacizumab single maintenance therapy for advanced NEC of the cervix.MethodsThis was a retrospective review of patients who received TC plus bevacizumab therapy for metastatic, recurrent, or persistent NEC of the cervix at seven institutions between 2015 and 2020. Relevant data were extracted from the patients' medical records and analyzed.ResultsSeven patients, including six with small‐cell NEC and one with large‐cell NEC, were included for analysis. Three patients received bevacizumab single maintenance therapy following TC plus bevacizumab therapy, whereas four patients did not receive bevacizumab single maintenance therapy. The median overall survival and progression‐free survival of the patients who received bevacizumab single maintenance therapy were longer than those of the patients who did not receive the therapy (34 months vs. 10.5 months and 19 months vs. 5 months, respectively). However, the patients who received bevacizumab single maintenance therapy had received cisplatin‐based chemotherapy previously.ConclusionsOn the premise that cisplatin‐based chemotherapy is administered as the first‐line treatment for advanced NEC of the cervix, bevacizumab single maintenance therapy following TC plus bevacizumab may be considered the second‐ or third‐line treatment. However, the risk of adverse events, such as intestinal perforation, should be discussed with patients.

Efficient expansion of tumor-infiltrating lymphocytes from gynecologic cancer

Abstract Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive immunotherapy potentially applicable to many types of solid tumors. Although gynecologic malignancies are promising targets for TIL therapy, its objective efficacy has not been established. Current TIL culture typically involves incubation of dissociated samples with high-dose IL-2 (HD-IL2) for weeks to enrich tumor-reactive T cells. While this protocol has been successfully used for melanoma TIL, it has not necessarily been optimized for other cancers. Here we investigated the method of efficiently expanding TILs derived from patients with gynecological cancers. TILs were incubated with HD-IL2 (HD-IL2-TILs) or stimulated with K562 cells expressing anti-CD3 mAb and CD80 (αCD3/CD80-TILs). We found that the αCD3/CD80-TILs showed significantly better proliferation than HD-IL2-TILs. The TIL populations that predominantly expanded upon αCD3/CD80 stimulation expressed high levels of PD-1 and CD28. CD28 co-stimulation was essential to overcome PD-1–mediated signals for growth suppression. We also identified DUSP4 as a negative regulator of TIL proliferation by downregulating ERK phosphorylation. The αCD3/CD80-TILs were reactive to tumor cells as shown by IFN-γ secretion and CD107a expression. Moreover, the αCD3/CD80-TILs were efficiently transduced with a chimeric cytokine receptor that we had previously developed to provide constitutive IL-7 signaling, resulting in superior in vivo persistence and antitumor effects without exogenous cytokine support in mouse models. Collectively, this study shows that direct stimulation of TILs with anti-CD3 mAb and CD28 co-stimulation achieves efficient expansion of tumor-reactive TILs. Genetic engineering of cytokine signaling in TILs may further enhance TIL functions and replace cytokine administration after TIL infusion.

Diagnostic accuracy and prognostic factors of uterine serous carcinoma in Japanese women: a multi-center study

This multi-center retrospective study aimed to clarify the characteristics, diagnostic accuracy, treatment outcomes, and prognostic factors of uterine serous carcinoma (USC) in Japanese women. The medical records of 193 patients who were treated between 2006 and 2008 at 24 participating institutions in the Japanese Clinical Oncology Group were examined, and pathological slides of 188 patients were re-checked through central pathology review (CPR), hematoxylin-eosin staining, and immunohistochemistry. USC was confirmed in 144 of the 188 (76.6%) patients using CPR, and only 50% were correctly diagnosed preoperatively. Forty-three patients were diagnosed with non-serous carcinoma, whereas one patient had metastasis from another organ. The average age was 65.7 years, and 19% of patients had a history of other cancers. The incidence of stage III-IV disease was 52.8%, and lymph node metastasis was found in 28.5% of patients. Extrauterine spread and distant metastasis occurred in 39% and 14% of patients, respectively. The 2-year overall survival and progression-free survival (PFS) rates were 56% and 42%, respectively. The PFS of patients with stage I and II who underwent complete staging surgery was 92.3%, and that of those without lymph node dissection or omentectomy was 33.3%. Patients with USC had a significantly worse prognosis than 43 patients with non-serous carcinoma. USC in Japanese women has characteristics different from those of endometrioid carcinoma, worse prognosis, and is difficult to diagnose preoperatively. Complete surgical staging is necessary even for early-stage disease. Additionally, new adjuvant treatment strategies, including molecular targeted therapy, should be explored.

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

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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT03517449.