Abstract Background and Purpose In Japan, cancer-gene profiling (CGP) tests, such as the OncoGuide NCC Oncopanel System, FoundationOne CDx Cancer Genome Profile (F-one), and FoundationOne Liquid CDx Cancer Genome Profile, are covered by insurance and clinically applied to promote cancer genomic medicine. Information from CGP tests is managed at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and shared with clinicians after discussions at the Expert Panel (EP). We provide an overview of the registered pediatric CNS tumors. Methods We extracted and analyzed CNS/brain data from the C-CAT registry from June 2019 to June 2022 for ages 0–19 years. Variables such as age, gender, histopathological diagnosis, CGP test type, ECOG Performance Status (PS), registration status, genetic abnormalities, and treatments were analyzed. Results Among 1133 patients of all ages with CNS tumors, 361 (31.9%) were aged 0–19 years; Of the 918 patients aged 0-19 years with any type of cancer, those with CNS tumors accounted for 34.2%; 188 patients were aged under 10 years, 173 patients were teenagers, 174 patients were males, 187 patients were females; PS was 0 in 47.9% of patients. The most common histopathological diagnoses were medulloblastoma, diffuse midline glioma and glioblastoma. Genetic abnormalities included TP53 mutations in 85 cases, H3F3A mutations in 38 cases, STK11 mutations in 36 cases, BRAF mutations in 33 cases, BRAF-KIAA1549 fusions in 24 cases, and TMB high in 16 cases. Seventy-six patients (21.1%) were offered treatment options in the EP, and 26 patients (7.2%) received the recommended treatment, including two in physician-initiated trials, four in company trials, eleven in treatments within insurance coverage, and eleven in others. Discussion This is the first report of genetic analysis of pediatric CNS tumors on a nationwide scale. Pediatric CNS tumors have a large number of registered cases; thus, drug development for them is urgently needed.
Abstract The majority of cervical adenocarcinomas are associated with human papillomavirus (HPV) mainly HPV types 18 and 16. Patients with gastric-type endocervical adenocarcinoma (GAS) have an aggressive clinical behavior, resulting in poor prognosis compared to those with HPV-associated usual type adenocarcinoma. Chemotherapy resistance to taxane and carboplatin-based regimen has also been reported, which poses a difficulty in managing GAS patients with metastatic lesion. We established patient-driven xenografts (PDX) of two GAS patients and evaluated protein biomarkers for drug development using immunohistochemistry staining. The pathological findings of the established PDX were confirmed by HE staining and special staining to be similar to the pathological findings obtained from the patients' surgical specimens. PDX was established 78 and 48 days after transplantation of patient tumor tissue into immunodeficient mice, respectively. HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A were stained for both PDX and patient-tumor samples to evaluate biomarkers for therapeutic targets. All staining results were consistent between patient tumor samples and PDX for both patients. Staining results for HER3 showed that both patients' tumors and the corresponding PDXs were 3+. Staining for HER2 was 1+ in both cases. In all PDX and patient-tumor samaples, PMS2, MSH6 and ARID1A showed no loss of protein expression, and PanTrk showed no protein expression. In addition, nine additional tumor tissue specimens from GAS patients diagnosed at our institution were stained for HER3 and HER2. HER3 was 3+ in 3 cases and 2+ in 6 cases, and HER2 was 3+ in 1 case, 2+ in 3 cases and 1+ in 5 cases. The present study showed overexpression of HER2 and HER3, suggesting a therapeutic potential of targeting HER2 and/or HER3 in GAS patients. We are next planning an in vivo study to develop therapies in GAS patients. Citation Format: Yuki Kojima, Hiroshi Yoshida, Toshihiro Okuya, Hitomi S. Okuma, Tadaaki Nishikawa, Maki Tanioka, Kazuki Sudo, Emi Noguchi, Tatsunori Shimoi, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa, Yasuhiro Fujiwara, Kan Yonemori, Tomoyasu Kato. Characterization based on therapeutic target biomarkers of patients-driven xenografts model of gastric-type cervical adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2930.
Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in genes (i.e. ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair (NER) pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival [hazards ratio (HR) = 1.75, 95% confidence interval (95% CI) = 1.07–2.86] and recurrence-free survival (HR = 2.17, 95% CI = 1.19–3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR = 1.60, 95% CI = 1.08–2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose–response manner (Ptrend = 0.006 and Ptrend < 0.000) in Japanese patients; specifically, compared with those with ≤1 risk genotypes, those with ≥2 risk genotypes showed markedly shorter overall survival (HR = 1.79, 95% CI = 1.18–2.70) and recurrence-free survival (HR = 2.80, 95% CI = 1.66–4.73). The association between ≥2 risk genotypes and shorter overall survival was not significant (HR = 1.26, 95% CI = 0.82–1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients.
Patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) have a poorer prognosis than those with squamous cell carcinoma (SCC). Erb-b2 receptor tyrosine kinase 3 (HER3) is a member of the epidermal growth factor receptor family and its expression is associated with unfavorable prognosis in several cancer types, including SCC of the cervix. As there is limited information on the prognostic value of HER3 for AC and ASC of the cervix, the present study aimed to evaluate the expression of HER3 and its impact on post-operative recurrence in patients with AC and ASC of the cervix. This retrospective study included 39 patients with early-stage AC and ASC who underwent primary surgery between January 1997 and December 2017. Immunohistochemical staining for HER3 was performed on formalin-fixed paraffin-embedded surgical specimens. The possible influence of HER3 expression on disease-free survival (DFS) was studied by using multivariate Cox regression with adjustment for established risk factors of post-operative recurrence. High expression of HER3 (HER3-high) was detected in 85.1% of cases of AC (23/27) and in 58.3% of cases of ASC (7/12). The median follow-up duration was 63.1 months and Kaplan-Meier analysis indicated that the 5-year DFS rates of patients with AC and ASC of the cervix were 56.7% in patients with HER3-high and 77.8% in patients with HER3-low (log rank, P=0.20). On multivariate analysis, HER3-high [hazard ratio (HR)=6.32, 95% CI: 1.10-36.26, P=0.039), pelvic lymph node metastasis (HR=7.61, 95% CI: 2.07-28.00, P=0.002) and vascular invasion (HR=4.28, 95% CI: 1.12-16.31, P=0.033) were indicated to be independent predictors of DFS. To date, the present study is the most comprehensive analysis to evaluate the expression of HER3 in patients with early-stage AC and ASC of the cervix. The results suggested that HER3 overexpression may be an independent risk factor for post-operative recurrence. However, these results and the prognostic value of HER3 should be confirmed in a larger sample.
<b><i>Background:</i></b> Nearly 50% of gastric cancer patients are diagnosed with advanced gastric cancer (AGC). Therapy is palliative but results in ill effects. The median overall survival (OS) of AGC patients is often <12 months. It is unclear if the early initiation of therapy in all AGC patients is beneficial. <b><i>Methods:</i></b> A retrospective analysis of AGC patients in our database was carried out. The patients were divided into two groups: asymptomatic or symptomatic. We sought to assess whether the delay of systemic therapy was harmful in asymptomatic patients. <b><i>Results:</i></b> A total of 135 patients were analyzed. Most patients were symptomatic (68%), males (67%), and had low ECOG scores (0-1; 85%). In univariate analyses, ECOG performance status 0 (p = 0.005), delayed initiation of therapy (p = 0.03), and lack of symptoms (p = 0.03) were associated with a longer OS. The multivariate model for OS identified only ECOG performance status as an independent prognosticator of longer OS (p = 0.02). Asymptomatic patients who had delayed (≥4 weeks) systemic therapy had an OS rate of 77% at 1 year compared to 58% for patients treated within 4 weeks (p = 0.47). <b><i>Conclusion:</i></b> Symptomatic AGC patients had a poor outcome compared to asymptomatic AGC patients. Treatment delay in asymptomatic patients had no detrimental effect on OS, suggesting that the timing of therapy can be based on patient selection.
Introduction: Next-generation sequencing (NGS) is commonly used in clinical practice to decide treatment based on genomic information. This study was performed to optimize the proportion of actionable gene profiling and treatment based on genetic alterations in breast cancer at one of cancer centers in Japan. Methods: Patients with breast cancer who reported NGS results at one of cancer centers in Japan from August 2019 to December 2023 were retrospectively investigated by reviewing their electronic medical records. Patients were examined using the OncoGuideTM NCC Oncopanel System, FoundationOne® CDx, or FoundationOne® Liquid CDx. The evidence levels for drug recommendation were added for each gene alteration according to the guidelines from three Japanese oncology-related societies. ‘’Actionable alterations’’ were those at evidence levels A–D, including high microsatellite instability and high tumor mutation burden status. “Patients with recommended drug” (approved, investigational, and off‐label drugs) were defined as those who were selected by the Molecular Tumor Board. Results: Of the 106 patients, 54 were tested using the NCC Oncopanel System and 50 using FoundationOne CDx. The most frequent alterations were TP53 mutations (52.8%) and PIK3CA mutations (31.1%). Of the 56 patients (52.8%) with recommended drugs, 11 (10.4%) received genome-matched therapy and only three (2.8%) participated in clinical trials. The most common reason for not receiving genome-matched therapy was patient refusal for personal reasons, although clinical trials were available (18 patients). Conclusion: The top reasons for patients not receiving the recommended genome-matched therapy were factors related to the patient, including a number of prior treatments higher than what was allowed by the eligibility criteria of the clinical trials, and poor physical condition. Most patients received four or more regimens of cytotoxic chemotherapy before NGS. NGS is only available at the late phase of treatment in Japan, which would constitute a problem for the treatment of breast cancer.
Abstract Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)
