記述言語：英語  

DOI： 10.1111/pin.13377

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記述言語：英語  

We report a case of rare and aggressive ovarian carcinosarcoma with a germline pathogenic BRCA2 variant. A patient with a history of breast cancer who developed an inflammatory ovarian tumor with peritonitis carcinomatosis involving the appendix suffered from cachexia. Following three cycles of weekly paclitaxel and carboplatin chemotherapy, emergency surgery was required owing to sepsis. Bilateral salpingo-oophorectomy, total hysterectomy, appendectomy, and small intestine adhesiolysis were performed. Histologically, the tumor comprised an admixture of carcinomatous and sarcomatous components, with involvement of the appendix, which had caused perforation and abscess formation. The final diagnosis was ovarian carcinosarcoma with a germline pathogenic BRCA2 variant, c.658_659del (p.Val220fs). The patient responded completely to adjuvant chemotherapy. A combination of chemotherapy and surgery might be beneficial to patients with ovarian carcinosarcoma and germline pathogenic BRCA2 variants with a poor general condition. This is the first report of ovarian carcinosarcoma with a germline pathogenic BRCA2 variant that responded favorably to chemotherapy.

DOI： 10.1111/jog.15736

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although circulating tumour DNA (ctDNA)-based next-generation sequencing (NGS) is a less invasive method for assessing ESR1 mutations that are essential mechanisms of endocrine therapy resistance in patients with oestrogen receptor-positive breast cancer, adequate amounts of DNA are required to assess polyclonal ESR1 mutations. By combining a peptide nucleic acid and locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamping assay, we have developed a novel detection system to screen for polyclonal ESR1 mutations in ctDNA. A validation assay was prospectively performed on clinical samples and compared with the NGS results. The PNA-LNA PCR clamp assay was validated using six and four blood samples in which ESR1 mutations were detected by NGS and no mutations were detected, respectively. The PNA-LNA assay results were comparable with those of NGS. We prospectively assessed the concordance between the PNA-LNA PCR clamp method and NGS. Using the PNA-LNA PCR clamp method, ESR1 mutations were detected in 5 out of 18 samples, including those in which mutations were not detected by NGS due to small amounts of ctDNA. The PNA-LNA PCR clamping method is a highly sensitive and minimally invasive assay for polyclonal ESR1 mutation detection in the ctDNA of patients with breast cancer.

DOI： 10.3390/diagnostics13122040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mesothelin (MSLN) is a cell-surface glycoprotein found in various solid tumours. Cancer therapies targeting MSLN have been developed in recent years; however, the available information on MSLN expression in cervical cancer is limited. This study aimed to evaluate MSLN expression in various histological types of cervical cancer and examine its relationship with prognosis. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between January 2000 and December 2020 at our institution. MSLN expression was evaluated by immunohistochemistry using clone SP74 and defined as positive if MSLN was expressed at any intensity. High MSLN expression was defined as an intensity of ≥ 2 + in ≥ 30% of tumour cells. The association between MSLN expression and clinicopathological factors was evaluated. RESULTS: Overall, 123 patients were identified, and 140 tumour samples, including 17 paired primary and metastatic samples, were evaluated. Concerning histological type, 67 patients had squamous cell carcinoma (SCC), whereas 56 had non-SCC. MSLN expression was observed in 98.4% (121/123) of primary tumours. High MSLN expression was observed in 63.4% of samples (78/123), but it differed between the histological types (49.2% for SCC vs. 80.4% for non-SCC, p < 0.001). There was a significant correlation between MSLN expression in primary and metastatic lesions (Rs = 0.557, p = 0.015). In patients with common histological types, overall survival (OS) was shorter in the high MSLN expression group than in the low MSLN expression group (hazard ratio, 3.53; 95% confidence interval, 1.16-15.3, p = 0.03). CONCLUSIONS: MSLN was highly expressed in patients with cervical cancer, especially in those with non-SCC. High MSLN expression in the primary lesion was significantly associated with poor OS, and its expression was maintained in metastatic lesions. Our findings indicate that MSLN may be an attractive therapeutic target for cervical cancer. TRIAL REGISTRATION: Retrospectively registered. 2014-393. 1 June 2015.

DOI： 10.1186/s12885-022-10277-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Stromal tumor-infiltrating lymphocytes (TILs) are independent prognostic factors in systemically untreated early-stage triple-negative breast cancer (TNBC). Other immune biomarkers including CD8, CD20, programmed cell death-ligand 1 (PD-L1), and tertiary lymphoid structures (TLS) are also reported to be associated with prognosis. However, whether combining other immune biomarkers with TILs would allow for further prognostic stratification is unknown. METHODS: We retrospectively analyzed 125 patients with early-stage TNBC not receiving perioperative chemotherapy. Stromal TILs and TLS were evaluated on hematoxylin-eosin slides. PD-L1 expression was evaluated using the SP142 assay. CD8 and CD20 were assessed by immunohistochemistry and counted by digital pathology. RESULTS: Immune biomarker levels were positively correlated (p < 0.001). Adding CD8 and PD-L1 to multivariable analysis including clinicopathological factors (stage and histological grade) and TILs significantly improved the prognostic model (likelihood ratio χ2 = 9.24, p = 0.01). In Cox regression analysis, high CD8 was significantly associated with better prognosis [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48-0.98, p = 0.04], and PD-L1 positivity was significantly associated with worse prognosis (HR 4.33, 95%CI 1.57-11.99, p = 0.005). Patients with high CD8/PD-L1 (-) tumors had the most favorable prognosis [5 year invasive disease-free survival (iDFS), 100%], while patients with low CD8/PD-L1( +) tumors had the worst prognosis (5 year iDFS, 33.3%). CONCLUSION: CD8 and PD-L1 levels add prognostic information beyond TILs for early-stage TNBC not receiving perioperative chemotherapy. CD8-positive T cells and PD-L1 may be useful for prognostic stratification and in designing future clinical trials of TNBC.

DOI： 10.1007/s10549-022-06787-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Folate receptor α (FRα) is a membrane protein expressed in various solid tumors but has limited expression in normal cells. Therefore, FRα is an attractive target for cancer treatment. This study aimed to investigate the relationship between FRα expression and the clinicopathological characteristics and survivals of cervical cancer. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between 2000 and 2020 at our institution. Immunohistochemical staining of FRα was performed using an anti-folate-binding protein/FBP antibody. FRα-positive staining was defined as ≥5% of tumor staining and FRα-high as ≥50% tumor staining with ≥2+ intensity. The association between FRα expression and survival was assessed using multivariate Cox regression analysis, adjusting for established prognostic factors. RESULTS: Overall, 123 patients were identified, and 140 tumor samples, including 17 paired primary and metastatic samples, were evaluated. As histological types, 67 patients had squamous cell carcinoma (SCC), and 56 patients had non-SCC. All primary tumors were FRα-positive. High FRα expression was observed in 25% of the cases and differed according to histology (SCC vs. non-SCC, 14.9% vs. 37.5%, p=0.004). FRα expression was significantly higher in metastatic tumors than in primary (170 [IQR, 140-205] vs. 125 [IQR, 110-150], p=0.0006). High FRα expression was significantly associated with worse overall survival (hazard ratio, 6.73; 95% confidence interval, 2.21-20.53; p=0.001). CONCLUSION: In cervical cancer, FRα expression was elevated in metastatic tumors and high expression was associated with a worse prognosis. Our study supports the development of FRα-targeted therapy for advanced cervical cancer.

DOI： 10.3802/jgo.2022.33.e82

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. METHODS: Patients received E7389-LF 2.0 mg/m2 every three weeks. Tumour assessments were conducted every six weeks by the investigator by Response Evaluation Criteria in Solid Tumours v1.1. All adverse events were monitored and recorded. Serum biomarker assessments were conducted. RESULTS: Of 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6-55.9) for all patients and 42.9% (95% CI: 21.8-66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9-8.3). The median overall survival was 18.3 months (95% CI: 13.2-not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point. CONCLUSION: E7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia. GOV NUMBER: NCT03207672.

DOI： 10.1016/j.ejca.2022.03.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Synovial sarcoma predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic synovial sarcoma. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with synovial sarcoma. METHODS: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic synovial sarcoma who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated. RESULTS: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for > 6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively. CONCLUSION: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with synovial sarcoma was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for synovial sarcomas.

DOI： 10.1159/000524500

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Eribulin or capecitabine monotherapy is the next cytotoxic chemotherapy option for patients with metastatic or recurrent breast cancer who have previously received an anthracycline or a taxane. However, it is unclear what factors can guide the selection of eribulin or capecitabine in this setting, and prognostic factors are needed to guide appropriate treatment selection. The neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor for eribulin-treated patients, although it is unclear whether it is a prognostic factor for capecitabine-treated patients. Therefore, we analysed the ability of the NLR to predict oncological outcomes among patients who received capecitabine after previous anthracycline or taxane treatment for breast cancer. METHODS: We retrospectively reviewed the medical records of patients with metastatic or recurrent breast cancer who had previously received anthracycline or taxane treatment at the National Cancer Center Hospital between 2007 and 2015. Patients were included if they received eribulin or capecitabine monotherapy as first-line, second-line, or third-line chemotherapy. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. RESULTS: Between 2007 and 2015, we identified 125 eligible patients, including 46 patients who received only eribulin, 34 patients who received only capecitabine, and 45 patients who received eribulin and capecitabine. The median follow-up period was 19.1 months. Among eribulin-treated patients, an NLR of <3 independently predicted better OS. Among capecitabine-treated patients, an NLR of <3 independently predicted better PFS but not better OS. In addition, a lymphocyte-to-monocyte ratio of ≥5 was associated with better PFS and OS. CONCLUSIONS: To the best of our knowledge, this is the first study to evaluate whether the NLR is a prognostic factor for capecitabine-treated patients with metastatic or recurrent breast cancer. However, the NLR only independently predicted PFS in this setting, despite it being a useful prognostic factor for other chemotherapies.

DOI： 10.1186/s12885-021-09112-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: BRCA1 c.5096G>A (p. Arg1699Gln) (hereinafter BRCA1 R1699Q) is classified as a pathogenic genetic variant despite its lower penetrance of breast and ovarian cancers compared to other BRCA1 variants. However, this mutation is currently reported as a 'special interpretation' variant in the BRACAnalysis® because the response to platinum agents and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors remains unknown in patients with this mutation. CASE PRESENTATION: We present a case of stage IIIc high-grade primary peritoneal cancer in a 69-year-old woman with germline BRCA1 R1699Q variant. She received platinum-containing chemotherapy followed by surgery. Eight months later, the patient experienced recurrence and received six cycles of chemotherapy and olaparib maintenance therapy. However, the disease progressed after only 5 months, and she received another chemotherapy drug. This patient responded slightly to platinum agents and had shorter progression-free survival on olaparib compared with clinical trial data. myChoice® CDx also showed Genomic Instability Score (GIS) was 50. This patient had no other gene mutations which could cause homologous recombination deficiency. CONCLUSION: This is the first report of the clinical outcome of PARP inhibitor and platinum-containing chemotherapy in a patient with a BRCA1 R1699Q variant. Despite BRCA1 mutation and high GIS, used as indicators of drug sensitivity, the recurrent tumor did not respond well to platinum agents and olaparib. BRCA1 R1699Q variant could differ from others in cancer risk and in drug response. Further studies are needed to confirm these observations.

DOI： 10.1016/j.ctarc.2022.100587

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media {LLC}  

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported. METHODS: We retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy. RESULTS: The median age at treatment initiation was 45 years (range 18-74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation. CONCLUSIONS: The EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement.

DOI： 10.1007/s10147-021-02021-8

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記述言語：英語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer. EXPERIMENTAL DESIGN: Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012). CONCLUSIONS: In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.

DOI： 10.1158/1078-0432.CCR-20-4102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.

DOI： 10.1038/s41523-021-00258-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach. Patients and Methods: Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS. Results: Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS. Conclusion: Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers. Clinical Registration: [https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

DOI： 10.3389/fonc.2021.732525

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors. PATIENTS AND METHODS: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression. RESULTS: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. CONCLUSION: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

DOI： 10.1200/PO.20.00383

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48-22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99-14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies.

DOI： 10.3892/ol.2020.12200

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.3892/ol.2020.11899

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following T-DM1 and clarify the predictive factors of their prognosis.We retrospectively identified patients with HER2-positive MBC who received T-DM1 between April 1, 2014, and December 31, 2018, at the National Cancer Center Hospital, and focused on the population that received another line of therapy following T-DM1 discontinuation.Thirty patients were available for the outcome analysis. Median progression-free survival (PFS) of the first subsequent therapy was 6.0 months [95% confidence interval (95% CI) 4.1-6.4], whereas the median overall survival (OS) from the first subsequent therapy was 20.6 months (95% CI 13.5 months to not reached). We divided the patients into 2 groups according to their PFS with T-DM1 treatment and compared their PFS with the subsequent therapy. The results revealed a significant difference in the median PFS with the first subsequent treatment between patients with the PFS of less than and more than 3 months [5.1 (95% CI 1.7-6.2) vs 6.2 (95% CI 4.0-11.3) months, P = .03].This is the first study to evaluate the survival outcomes of post-T-DM1 therapy in Japanese patients with HER2-positive MBC. A short PFS with T-DM1 might affect the PFS with a treatment after T-DM1.

DOI： 10.1097/MD.0000000000022331

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Homologous recombination deficiency (HRD), which influences the efficacy of PARP inhibitor- and platinum agent-based therapies, is a prevalent phenotype of breast cancer in adolescents and young adults (AYAs; 15-39 years old). However, HRD score, indicating HRD status, is not routinely assessed in the breast oncology clinic, particularly in patients without germline BRCA1/2 mutations. Hence, we sought to develop a model for determining HRD status based on genetic and clinicopathological factors. METHODS: Subjects were our own cohort of 46 Japanese AYA breast cancer patients and two existing breast cancer cohorts of US and European patients. Models for prediction of the HRD-high phenotype, defined as HRD score ≥ 42, were constructed by logistic regression analysis, using as explanatory variables genetic and clinicopathological factors assessable in the clinical setting. RESULTS: In all three cohorts, the HRD-high phenotype was associated with germline BRCA1/2 mutation, somatic TP53 mutation, triple-negative subtype, and higher tumor grade. A model based on these four factors, developed using the US cohort, was validated in the Japanese and European AYA cases: area under the receiver operating characteristic curve [AUC] was 0.90 and 0.96, respectively. A model based on three factors excluding germline BRCA1/2 mutation also yielded high-predictive power in cases from these two cohorts without germline BRCA1/2 mutations: AUC was 0.92 and 0.90, respectively. CONCLUSIONS: The HRD-high phenotype of AYA breast cancer patients can be deduced from genomic and pathological factors that are routinely examined in the oncology clinic, irrespective of germline BRCA1/2 mutations.

DOI： 10.1007/s10549-020-05716-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability normally preclude processing samples across multiple technologies, making it challenging to directly evaluate performance and whether data from different platforms can be reliably compared or integrated. METHODS: This study describes our experiences of nine new and established mRNA profiling techniques including Lexogen QuantSeq, Qiagen QiaSeq, BioSpyder TempO-Seq, Ion AmpliSeq, Nanostring, Affymetrix Clariom S or U133A, Illumina BeadChip and RNA-seq of formalin-fixed paraffin embedded (FFPE) and fresh frozen (FF) sequential patient-matched breast tumour samples. RESULTS: The number of genes represented and reliability varied between the platforms, but overall all methods provided data which were largely comparable. Crucially we found that it is possible to integrate data for combined analyses across FFPE/FF and platforms using established batch correction methods as required to increase cohort sizes. However, some platforms appear to be better suited to FFPE samples, particularly archival material. CONCLUSIONS: Overall, we illustrate that technology selection is a balance between required resolution, sample quality, availability and cost.

DOI： 10.1186/s12859-020-3365-5

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記述言語：英語  

Background: Metaplastic breast carcinomas are rare and carry poor prognoses. They are also more aggressive than other breast cancers and are known for their resistance to chemotherapy. Prolonged treatment with dabrafenib and trametinib is a therapy for malignant melanoma that improves the progression-free survival and overall survival. Such molecular-targeted therapies are also being developed for cancers with BRAF mutation, a driver of malignant melanoma. Case Presentation. A 57-year-old woman with metaplastic breast cancer and chemotherapy-refractory massive pleural effusion. After contained anthracycline regimen failure, her breast cancer progressed to an advanced stage. We ordered next-generation sequencing- (NGS-) based tumor molecular profiling from core needle biopsy of the breast. The NGS report indicated the presence of a BRAF V600E mutation. After initiation of dabrafenib and trametinib, her symptom and the pleural effusion were decreased. The first assessment of CT scans showed a decreased pleural effusion and shrunken subcutaneous lesions. Approximately 2 weeks later, a new lesion appeared. She died from 12 weeks after initiation of dabrafenib and trametinib treatment. Conclusion: To the best of our knowledge, this is the first report of BRAF mutation breast cancer treated with dabrafenib and trametinib and it heralds the possibility of targeted therapy for rare breast cancers.

DOI： 10.1155/2020/2518383

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma. METHODS: This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma. RESULTS: The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death. CONCLUSION: IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We propose a statistical boosting method, termed I-Boost, to integrate multiple types of high-dimensional genomics data with clinical data for predicting survival time. I-Boost provides substantially higher prediction accuracy than existing methods. By applying I-Boost to The Cancer Genome Atlas, we show that the integration of multiple genomics platforms with clinical variables improves the prediction of survival time over the use of clinical variables alone; gene expression values are typically more prognostic of survival time than other genomics data types; and gene modules/signatures are at least as prognostic as the collection of individual gene expression data.

DOI： 10.1186/s13059-019-1640-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown. METHODS: A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC50 doses, and MMTV/Neu luminal mouse tumors were untreated or treated with entinostat until progression. We investigated these models using their gene expression profiling by microarray and copy number by arrayCGH. We also utilized the network-based DawnRank algorithm that integrates DNA and RNA data to identify driver genes of resistance. The impact of candidate drivers was investigated in The Cancer Genome Atlas and METABRIC breast cancer datasets. RESULTS: Luminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17-23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival. CONCLUSIONS: Entinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.

DOI： 10.1186/s13073-018-0597-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy.Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures.Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features.Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292-304. ©2018 AACR.

DOI： 10.1158/1078-0432.ccr-17-3431

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients.
Methods: We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis.
Results: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged &gt;= 60 years and 89 patients were aged &lt; 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002).
Conclusions: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

DOI： 10.1016/j.jbo.2017.08.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

The aim of this study is to evaluate the outcome and safety of the multidisciplinary strategy using cisplatin plus dose-dense paclitaxel (dose-dense TP) before and after radical hysterectomy (RH) for stage IB2, IIA2, or IIB patients with cervical cancer. In the dose-finding phase, 12 patients received 3 cycles of cisplatin (75 mg/m2, day 1) with paclitaxel (70 or 80 mg/m2, days 1, 8, and 15) every 21 days as neoadjuvant chemotherapy (NAC). In the phase II study, 51 patients received 3 cycles of dose-dense TP at the recommended dose as NAC, and another 2 cycles of the same regimen after RH. The primary endpoint was 2-year progression-free survival (PFS). The secondary endpoints were 2-year overall survival (OS), adverse events (AEs), response rate (RR), and pathological complete response (pCR) rates. The recommended dose of paclitaxel at dose-finding phase was 80 mg/m2. In the phase II study, 34 patients (66.7%) had FIGO stage IIB disease. The RR and pCR rates were 94 and 28%. With a median follow-up duration of 58 months, each of the 2- and 5-year PFS rates was 88.2%, the 2- and 5-year OS rates were 94.1 and 88.2%, respectively. The incidence of grade 3/4 AEs was neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). Dose-dense TP before and after RH achieved a good long-term survival and was feasible for patients with locally advanced cervical cancer.

DOI： 10.1007/s12032-017-0992-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ncomms15479

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities.

DOI： 10.1038/ncomms14864

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Platinum agents are essential for treating gynecological malignancies, particularly ovarian cancer. However, multiple carboplatin doses may cause hypersensitivity reactions (HSRs). Carboplatin desensitization prevents life-threatening HSRs and promotes the successful completion of planned chemotherapy. METHODS: Since January 2010, carboplatin desensitization was performed at our institution. Solutions with 1/1000, 1/100, and 1/10 dilutions of carboplatin and an undiluted solution were prepared in 250 mL of 5% glucose. Each solution was administered as a 1-h intravenous infusion (4-step 4-h protocol). This retrospective analysis was approved by the institutional review board. RESULTS: From January 2010 to December 2013, 20 patients with gynecological malignancies (median age 62 years, range 43-74 years) received desensitization treatment. The International Federation of Gynecology and Obstetrics stages at presentation were I, II, III, and IV in 1, 1, 15, 13 patients, respectively. During first-line and second-line treatments, 3 and 17 patients, respectively, experienced carboplatin-induced HSRs. The median carboplatin cycle number was 11 (range 2-16). In the first desensitization cycle, 17 (85%) patients completed treatment without adverse events, 2 experienced Grade 1 HSRs but completed treatment, and 1 experienced Grade 3 HSR and discontinued treatment. The first desensitization cycle completion rate was 95%. Of 83 desensitization cycles administered, 79 (95.2%) were completed. No treatment-related deaths occurred. CONCLUSIONS: Most patients completed the planned chemotherapy. Our protocol could be conducted safely with shorter duration and simpler procedures than previous protocols. Carboplatin desensitization seems beneficial for patients with a history of carboplatin-induced HSRs; however, the risk of HSR recurrence still remains. Desensitization should therefore be performed only by well-trained staff.

DOI： 10.1007/s10147-014-0731-1

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/jco.2015.33.15_suppl.e16515

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10549-014-3121-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CHURCHILL LIVINGSTONE  

Objective: For patients with HER2-positive breast cancer, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is unclear when stratified by hormonal receptor (HR) status; however, the impact of pCR on survival when stratified by hormonal receptor (HR) status is uncertain.Patients and methods: This multicenter retrospective study investigated the predictors of pCR and its prognostic value in Japanese patients 366 HER2-positive breast cancer who received NAC. pCR was defined as no invasive residual tumor in the breast or axilla.Results: Median follow-up was 55 months. Multivariate analysis revealed that HR status (OR, 0.37; p < 0.001) was one of the independent predictors of pCR. Five-year recurrence-free survival was higher in HR-negative patients with pCR (93%) than in those without pCR (68%), and pCR was independently prognostic (hazard ratio, 0.32; p = 0.005). However, 5-year recurrence-free survival was not different between HR-positive patients with pCR (94%) and those without pCR (84%), and pCR was not significantly prognostic (hazard ratio, 0.53; p = 0.39). In addition, 5-year overall survivals were high and similar (97% in pCR, 94% in non-pCR). Among 204 patients treated with neoadjuvant trastuzumab, pCR was not significantly prognostic in the HR-positive group (hazard ratio, 0.63; p = 0.56).Conclusion: Our study suggested that the HER2-positive HR-positive patients had a good prognosis despite the lower achievement rate of pCR, whose prognostic impact was smaller than that in the HER2-positive HR-negative patients. The treatment strategy for HER2-positive breast cancer can be stratified by HR status. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.breast.2014.03.008

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The concept of "platinum sensitivity" has been widely applied in the management of recurrent ovarian cancer. This study aimed to evaluate the applicability of this concept to recurrent endometrial cancer. PATIENTS AND METHODS: In this multicenter retrospective cohort study, the clinical data of patients with recurrent endometrial cancer, who had a history of receiving first-line platinum-based chemotherapy and who received second-line platinum-based chemotherapy at the time of recurrence between January 2005 and December 2009 were reviewed. RESULTS: A total of 262 patients from 30 centers with initial FIGO stage classifications of I (29), II (23), III (122), and IV (88) were enrolled. In total, 153 endometrioid adenocarcinomas, 34 serous adenocarcinomas, 17 clear cell adenocarcinomas, 36 carcinosarcomas, and 22 "other" tumors were documented. The response rates for patients with platinum-free intervals of <6 months, 6-11 months, 12-23 months, and ≥24 months were 25%, 38%, 61%, and 65%, respectively. The median progression-free survival after second-line platinum-based chemotherapy for patients with platinum-free intervals of <12 months and ≥12 months was 4.4 (95% confidence interval (CI)=3.7-5.8) months and 10.3 (95% CI=8.2-12.6) months, respectively (log-rank P<0.0001), and the median overall survival was 13.8 (95% CI=10.6-18.1) months and 40.9 (95% CI=25.3-54.2) months, respectively (log-rank P<0.0001). CONCLUSION: Platinum-free interval is a predictor of response and survival after second-line platinum-based chemotherapy in patients with recurrent endometrial cancer. The concept of "platinum sensitivity" could be applicable to recurrent endometrial cancer.

DOI： 10.1016/j.ygyno.2013.09.021

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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DOI： 10.1038/bjc.2013.400

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. METHODS: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). RESULTS: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. CONCLUSIONS: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.

DOI： 10.1371/journal.pone.0063249

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors. METHODS: Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations. RESULTS: BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively. CONCLUSIONS: Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.

DOI： 10.1007/s00280-012-1932-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). METHODS: This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated. RESULTS: Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response. CONCLUSIONS: Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-naïve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.

DOI： 10.1007/s10637-011-9715-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. METHODS: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. RESULTS: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks). CONCLUSION: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.

DOI： 10.1007/s00280-012-1846-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Ridaforolimus is a non-prodrug mTOR inhibitor. The safety, pharmacokinetics (PK), and antitumor activity of oral ridaforolimus were assessed in Japanese patients with refractory solid tumors. METHODS: Ridaforolimus (20 or 40 mg) was administered as a single dose on Day 1, followed by once daily dosing five times a week for a 3-week cycle beginning on Day 8. Full PK sampling was performed on Days 1 and 26. RESULTS: Thirteen patients (7 at 20 mg and 6 at 40 mg) were enrolled. The median treatment duration was 82 days. The most common drug-related adverse events were stomatitis, hypertriglyceridemia, and proteinuria. Two patients had dose-limiting toxicities (grade 3 stomatitis at 20 mg, and grade 3 anorexia and vomiting at 40 mg). Four patients had grade 1 interstitial pneumonitis. Ridaforolimus in the whole blood was rapidly absorbed and slowly eliminated with a half-life of approximately 56-58 h after a single dose. Two patients (with non-small cell lung cancer and angiosarcoma, respectively) achieved a partial response, and five patients (one with thymic cancer and four with soft tissue sarcomas) had a stable disease for ≥ 16 weeks. CONCLUSIONS: Ridaforolimus was well tolerated up to a dose of 40 mg in Japanese patients. Preliminary evidence of antitumor activity was observed for patients with solid tumors. Further investigation at this dose is warranted.

DOI： 10.1007/s00280-011-1788-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed.

DOI： 10.1111/j.1349-7006.2011.02179.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: After the front-line platinum-based regimens including concurrent chemoradiotherapy (CCRT) in patients with advanced or recurrent cervical cancer, platinum-based regimens are often used again. PATIENTS AND METHODS: We retrospectively studied the predictors of response to second platinum therapy and prognostic factors of survival of 65 women who had received ≥ 2 platinum-based regimens in order to evaluate the effects of platinum-free interval (PFI), i.e., the interval between the platinum therapies. RESULTS: The median survival and PFI were 11.0 and 11.1 months, respectively. The response rate was 42% overall and 36% in the 36 patients who had received CCRT. The response rate increased in parallel with the length of the PFI. Multivariate analyses showed a PFI for ≥ 12 months (odds ratio [OR] = 0.20), a PS of 0 (OR = 0.16) and a maximum tumor diameter ≤ 30 mm (OR = 0.18) were predictive of response. Multivariate analyses also revealed a PFI for ≥ 6 months (hazard ratio [HR] = 0.44) and a PS of 0 (HR = 0.30) were prognostic of survival. CONCLUSION: Our exploratory study demonstrated that PFI has both predictive and prognostic value for second platinum therapy in patients with advanced or recurrent cervical cancer.

DOI： 10.1007/s00280-010-1494-7

PubMed

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00280-010-1506-7

PubMed

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12032-009-9389-3

PubMed

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bjc.6605769

PubMed

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記述言語：英語   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1535-7163.TARG-09-C37

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A myeloid leukemia cell line designated Kasumi-6 was established from the bone marrow cells of an individual with acute myeloid leukemia, subtype M2. Both the original leukemic cells and the Kasumi-6 cell line harbor a hemizygous point mutation in the gene encoding the CCAAT/enhancer binding protein alpha (C/EBPalpha), a critical myeloid transcriptional factor. The C to G transition at nucleotide 1063 of the C/EBPalpha gene results in amino acid transition R305P in the fork or hinge region between the DNA-binding basic region and the leucine zipper dimerization domain of the C/EBPalpha protein. The Kasumi-6 cells expressed both the p42 and p30 isoforms of the C/EBPalpha protein endogenously, but electrophoretic mobility shift assays demonstrated an absence of C/EBPalpha binding to its respective site. Exogenous expression of the mutant form of C/EBPalpha demonstrated that it was unable to bind DNA and activate transcription from a G-CSF receptor-luciferase reporter construct. Furthermore, coexpression of the wild-type and mutant forms revealed that the mutant form repressed reporter gene activation by the wild type in a dose-responsive manner. This was concomitant with a dose-responsive decrease in wild-type protein binding to the G-CSF receptor C/EBP site. The data suggest that the R305P alteration confers a dominant-negative property on the mutant C/EBPalpha protein whereby the mutant polypeptide heterodimerizes with the wild-type polypeptide and prevents it from binding to DNA, thus blocking transcriptional activation. The Kasumi-6 cell line can serve as a model to study the cellular and molecular biology of the non-t(8;21) M2 type of myeloid leukemia and can elucidate the role of mutated C/EBPalpha in leukemogenesis.

DOI： 10.1002/gcc.10161

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：英語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本婦人科腫瘍学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

Web of Science

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記述言語：日本語   出版者・発行元：(公財)大和証券ヘルス財団  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

Web of Science

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：日本癌学会  

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