Pub Date : 2019-02-15DOI: 10.1158/1538-7445.sabcs18-p3-03-16
S. Sahoo, M. Mir, Vm Sarode, Yisheng V. Fang, Y. Peng, K. Gwin, H. Hwang
{"title":"Abstract P3-03-16: Intraoperative evaluation of sentinel lymph nodes after neoadjuvant systemic therapy in breast cancer","authors":"S. Sahoo, M. Mir, Vm Sarode, Yisheng V. Fang, Y. Peng, K. Gwin, H. Hwang","doi":"10.1158/1538-7445.sabcs18-p3-03-16","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-p3-03-16","url":null,"abstract":"","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78123391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P5-12-17
K. Tozuka, S. Nagai, H. Matsumoto, Y. Hayashi, Kazuyuki Kubo, M. Tsuboi, A. Sato, K. Takai, X. Wang, Y. Yamada, Kenichi Inoue
{"title":"Abstract P5-12-17: Prognostic and predictive value of serum level of vascular endothelial growth factor-A in metastatic breast cancer patients treated with bevacizumab plus paclitaxel","authors":"K. Tozuka, S. Nagai, H. Matsumoto, Y. Hayashi, Kazuyuki Kubo, M. Tsuboi, A. Sato, K. Takai, X. Wang, Y. Yamada, Kenichi Inoue","doi":"10.1158/1538-7445.SABCS18-P5-12-17","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P5-12-17","url":null,"abstract":"","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78167333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.sabcs18-p5-12-15
E. Joung, J-H Yang, Jin-Seok Lee
{"title":"Abstract P5-12-15: Hepatic-metastatsis pattern as a prognositc marker in metastatic breast cancer","authors":"E. Joung, J-H Yang, Jin-Seok Lee","doi":"10.1158/1538-7445.sabcs18-p5-12-15","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-p5-12-15","url":null,"abstract":"","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80147817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P6-20-13
D. Lala, T. Haque, H. Feinman, J. Wu, Y. Wang, A. Dwyer, Thu H. Truong, C. Lange
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer related death in women. Around 5–10% of cases are metastatic at diagnosis, and close to 30% of patients with early stage disease will relapse with metastatic disease. Anti-estrogen therapy is an important treatment modality for hormone receptor-positive (HR+) metastatic breast cancer (mBCa) as mono- or combination (e.g. with CDK4/6 inhibitors) first-line (1L) therapy. Unfortunately, despite the high rate of clinical benefit in 1L therapy, disease progression still generally occurs and there remains a need for an efficacious 2L therapy. Although anti-estrogens continue to play a role in 2L treatment there is a critical need for targeting additional mechanisms in combination with anti-estrogens. Progesterone is a major mitogen in the adult human mammary epithelium and, in addition to ER, is a key driver of breast cancer cell proliferation. Thus, blocking both ER and PR would likely be an effective approach for inhibition of all hormone driven breast cancer cell proliferation. Onapristone is a unique PR full antagonist that is efficacious as an antitumor agent in multiple preclinical breast cancer models and exhibits additive/synergistic effects with antiestrogens. Here, we examine the effects of onapristone in in-vitro model systems in combination with CDK4/6 inhibitors. Methods: T47D cells were treated with various concentrations of onapristone or palbociclib in media containing 10%FBS.10 days after treatment cell viability was determined using Cell Titer Glo. Cells were also treated with increasing concentrations of palbociclib in the absence or presence of onapristone and analysed for cell proliferation after 10 days and for gene expression after 3 days of treatment.The effects of onapristone were also tested in soft agar anchorage-independent growth assays as well as 3D tumorsphere assays using ER+/PR+ MCF7 and BT474 cells -/+ onapristone for 21-28 days. Formed colonies or spheres were analyzed morphologically using cell stain and by quantifying the total number and size of colonies or spheres formed. Results:Onapristone inhibited T47D cell proliferation in a concentration-dependent manner. Additionally, it sensitized the cells to inhibition by CDK4/6 inhibitors in the preclinical in-vitro models. Onapristone also had a marked effect on downstream target genes in the cell-based models providing a mechanistic basis for the anti-proliferative effects. Onapristone also blocked progesterone-induced breast cancer cell survival in either soft agar or 3D tumorsphere assays with effects comparable to that of anti-estrogen (fulvestrant). Conclusions: Onapristone inhibits T47D proliferation and key target genes involved in cell proliferation. Additionally, onapristone enhances the anti-proliferative effects of palbociclib in-vitro. Previous studies have provided a clear rationale for combining onapristone and anti-estrogens in the clinic for the treatment of breast
乳腺癌是最常见的癌症，也是妇女癌症相关死亡的第二大原因。约5-10%的病例在诊断时已转移，近30%的早期疾病患者会复发并转移性疾病。抗雌激素治疗是激素受体阳性(HR+)转移性乳腺癌(mBCa)的重要治疗方式，可作为单用或联合(如与CDK4/6抑制剂)一线(1L)治疗。不幸的是，尽管1L治疗的临床获益率很高，但疾病进展仍然普遍发生，仍然需要有效的2L治疗。尽管抗雌激素继续在2L治疗中发挥作用，但迫切需要靶向与抗雌激素联合的其他机制。黄体酮是成人乳腺上皮中主要的有丝分裂原，除ER外，也是乳腺癌细胞增殖的关键驱动因素。因此，阻断ER和PR可能是抑制所有激素驱动的乳腺癌细胞增殖的有效方法。奥纳匹司通是一种独特的PR全拮抗剂，在多种临床前乳腺癌模型中作为抗肿瘤药物有效，并与抗雌激素具有加性/协同作用。在这里，我们研究了onapristone在体外模型系统中与CDK4/6抑制剂联合使用的效果。方法:在含10%胎牛血清的培养基中，用不同浓度的奥那匹司酮或帕博西尼处理T47D细胞。治疗10天后用细胞滴度Glo检测细胞活力。在没有或存在奥那匹司酮的情况下，细胞也用增加浓度的帕博西尼处理，并在10天后分析细胞增殖和在治疗3天后分析基因表达。使用ER+/PR+ MCF7和BT474细胞-/+ onapristone 21-28天，在软琼脂锚定不依赖生长试验和3D肿瘤球试验中检测onapristone的作用。形成的菌落或球体使用细胞染色和定量的总数和大小形成的菌落或球体的形态分析。结果:奥那匹司酮抑制T47D细胞增殖呈浓度依赖性。此外，在临床前体外模型中，它使细胞对CDK4/6抑制剂的抑制变得敏感。在基于细胞的模型中，奥纳匹司通对下游靶基因也有显著的影响，为其抗增殖作用提供了机制基础。在软琼脂或3D肿瘤球试验中，奥纳匹司通也能阻断黄体酮诱导的乳腺癌细胞存活，其效果与抗雌激素(氟维司汀)相当。结论:奥那普利斯通抑制T47D增殖及参与细胞增殖的关键靶基因。此外，onapristone在体外增强了palbociclib的抗增殖作用。以往的研究已经为临床应用奥纳匹司酮和抗雌激素联合治疗乳腺癌提供了明确的依据。我们的数据扩展了这些研究，为onapristone联合CDK4/6抑制剂(如palbociclib)作为治疗乳腺癌的有效新方法提供了额外的理论依据。引用本文:Lala D, Haque T, Feinman H, Wu J, Wang Y, Dwyer A, Truong T, Lange C.纯孕激素受体(PR)拮抗剂onapristone增强CDK4/6抑制剂在临床前体外乳腺癌模型中的抗增殖作用[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;癌症杂志，2019;79(4增刊):P6-20-13。
{"title":"Abstract P6-20-13: The pure progesterone receptor (PR) antagonist onapristone enhances the anti-proliferative effects of CDK4/6 inhibitors in preclinical in-vitro breast cancer models","authors":"D. Lala, T. Haque, H. Feinman, J. Wu, Y. Wang, A. Dwyer, Thu H. Truong, C. Lange","doi":"10.1158/1538-7445.SABCS18-P6-20-13","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P6-20-13","url":null,"abstract":"Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer related death in women. Around 5–10% of cases are metastatic at diagnosis, and close to 30% of patients with early stage disease will relapse with metastatic disease. Anti-estrogen therapy is an important treatment modality for hormone receptor-positive (HR+) metastatic breast cancer (mBCa) as mono- or combination (e.g. with CDK4/6 inhibitors) first-line (1L) therapy. Unfortunately, despite the high rate of clinical benefit in 1L therapy, disease progression still generally occurs and there remains a need for an efficacious 2L therapy. Although anti-estrogens continue to play a role in 2L treatment there is a critical need for targeting additional mechanisms in combination with anti-estrogens. Progesterone is a major mitogen in the adult human mammary epithelium and, in addition to ER, is a key driver of breast cancer cell proliferation. Thus, blocking both ER and PR would likely be an effective approach for inhibition of all hormone driven breast cancer cell proliferation. Onapristone is a unique PR full antagonist that is efficacious as an antitumor agent in multiple preclinical breast cancer models and exhibits additive/synergistic effects with antiestrogens. Here, we examine the effects of onapristone in in-vitro model systems in combination with CDK4/6 inhibitors. Methods: T47D cells were treated with various concentrations of onapristone or palbociclib in media containing 10%FBS.10 days after treatment cell viability was determined using Cell Titer Glo. Cells were also treated with increasing concentrations of palbociclib in the absence or presence of onapristone and analysed for cell proliferation after 10 days and for gene expression after 3 days of treatment.The effects of onapristone were also tested in soft agar anchorage-independent growth assays as well as 3D tumorsphere assays using ER+/PR+ MCF7 and BT474 cells -/+ onapristone for 21-28 days. Formed colonies or spheres were analyzed morphologically using cell stain and by quantifying the total number and size of colonies or spheres formed. Results:Onapristone inhibited T47D cell proliferation in a concentration-dependent manner. Additionally, it sensitized the cells to inhibition by CDK4/6 inhibitors in the preclinical in-vitro models. Onapristone also had a marked effect on downstream target genes in the cell-based models providing a mechanistic basis for the anti-proliferative effects. Onapristone also blocked progesterone-induced breast cancer cell survival in either soft agar or 3D tumorsphere assays with effects comparable to that of anti-estrogen (fulvestrant). Conclusions: Onapristone inhibits T47D proliferation and key target genes involved in cell proliferation. Additionally, onapristone enhances the anti-proliferative effects of palbociclib in-vitro. Previous studies have provided a clear rationale for combining onapristone and anti-estrogens in the clinic for the treatment of breast","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79154029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P4-06-23
Y. Moon, N. Park, J. Hur, K. Pandey, Y.-L. Cho, S.K. Kim, Sa Lee, Gw Son, Jm Jo, H. An
Background: With the increasing success of immune checkpoint blockades for cancer treatment, we increasingly need well-characterized preclinical models. Syngeneic mice models (with a fully competent immune system) have advantages that they are easily established and cost less, though they do not reflect genetic complexity of human tumors. We evaluated feasibility of syngeneic mice models of breast cancer by analyzing efficacy of immune checkpoint blockade and dynamic change of tumor immune microenvironment. Methods: We used syngeneic mice model of JC, 4T1, and EMT6 cells, which are all murine triple negative breast cancer in BALB/c mice. At the time when subcutaneous tumors reach at 50˜100mm^3, each mice models were divided into 2 groups for treatment versus no-treatment control. In the treatment group, mice version of anti-PD-1 antibody was intraperitoneally injected (q 3 days, x 6). Anti-tumor efficacy was monitored by measuring tumor volume. 9Tumor response9 was defined as a case with tumor volume less than that of control group by a standard error at a determined time point. Immune microenvironment was evaluated by measuring serum cytokines (IL-2, IL-6, IL-10, IFNγ, and TNFα) with legendplex and immune cells (CD3, CD4, CD8, CD56, and FOXP3) of peripheral blood with FACS before injection of PD-1 blockade, after 1st injection, and when euthanized. Tumor-infiltrating immune cells were evaluated with FACS, when euthanized. Results: The tumor response rate to PD-1 blockade was highest in the 4T1 model (54.5%, 6/11) compared to JC model (40%, 4/10) or EMT6 model (36.4%, 4/11). Bleeding 3 times and tumor obtainment when euthanized in each mouse were feasible for profiling of cytokines and immune cells. Although before treatment with PD-1 blockade, CD3+T cells in peripheral blood were slightly lower in 4T1 model (18.3±8.1%) than JC model (24.6±4.7%) or EMT6 model (27.9±6.3%), after injection of one dose of PD-1 blockade, CD3+T cells increased 1.5 times in 4T1 model (18.3% to 27.3%), whereas those CD3+T cells decreased slightly in JC model and EMT6 model. Dynamic changes were not observed in other subsets of peripheral immune cells in all 3 models. Serum TNFα (with statistical significance) and IFNγ (with borderline significance) were higher in responders than in non-responders or no-treatment control. Conclusions: Syngeneic mice models of breast cancer were feasible to investigate immune checkpoint blockades and monitor dynamic change of immune microenvironment. In this regard, such models may be used to evaluate immune checkpoint blockade-based combination therapy as well. Citation Format: Moon YW, Park N, Hur J, Pandey K, Cho YB, Kim SK, Lee SA, Son GW, Jo JM, An H-J. Feasibility of sygeneic mice models of breast cancer for research of immune checkpoint blockades [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-23.
背景:随着免疫检查点阻断治疗癌症的成功率越来越高，我们越来越需要具有良好特征的临床前模型。同基因小鼠模型(具有完全有效的免疫系统)的优点是易于建立且成本较低，尽管它们不能反映人类肿瘤的遗传复杂性。我们通过分析免疫检查点阻断的效果和肿瘤免疫微环境的动态变化来评价构建乳腺癌小鼠模型的可行性。方法:采用BALB/c小鼠三阴性乳腺癌细胞JC、4T1和EMT6的同基因小鼠模型。当皮下肿瘤达到50 ~ 100mm^3时，将每只小鼠模型分为治疗组和未治疗组。治疗组腹腔注射小鼠型抗pd -1抗体(q 3天，x 6天)，通过测量肿瘤体积监测抗肿瘤效果。9肿瘤反应9定义为在确定的时间点肿瘤体积小于对照组的标准误差。注射PD-1阻断剂前、第一次注射后和安乐死时，用流式细胞仪测定血清细胞因子(IL-2、IL-6、IL-10、IFNγ和TNFα)和外周血免疫细胞(CD3、CD4、CD8、CD56和FOXP3)，评价免疫微环境。在安乐死时，用流式细胞仪评估肿瘤浸润性免疫细胞。结果:4T1模型对PD-1阻断的肿瘤应答率(54.5%，6/11)高于JC模型(40%，4/10)或EMT6模型(36.4%，4/11)。在每只小鼠安乐死时出血3次和肿瘤获得是可行的细胞因子和免疫细胞谱。虽然PD-1阻断剂治疗前，4T1模型外周血CD3+T细胞含量(18.3±8.1%)略低于JC模型(24.6±4.7%)或EMT6模型(27.9±6.3%)，但注射1剂PD-1阻断剂后，4T1模型外周血CD3+T细胞含量增加1.5倍(18.3% ~ 27.3%)，而JC模型和EMT6模型外周血CD3+T细胞含量均略有下降。其他外周免疫细胞亚群在所有3种模型中均未观察到动态变化。反应组血清TNFα(有统计学意义)和IFNγ(有临界意义)高于无反应组和无治疗对照组。结论:用同基因乳腺癌小鼠模型研究免疫检查点阻断和监测免疫微环境的动态变化是可行的。在这方面，这些模型也可用于评估基于免疫检查点阻断的联合治疗。引文格式:Moon YW, Park N, Hur J, Pandey K, Cho YB, Kim SK, Lee SA, Son GW, Jo JM, An H-J。同基因乳腺癌小鼠模型用于免疫检查点阻断研究的可行性[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):P4-06-23。
{"title":"Abstract P4-06-23: Feasibility of sygeneic mice models of breast cancer for research of immune checkpoint blockades","authors":"Y. Moon, N. Park, J. Hur, K. Pandey, Y.-L. Cho, S.K. Kim, Sa Lee, Gw Son, Jm Jo, H. An","doi":"10.1158/1538-7445.SABCS18-P4-06-23","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P4-06-23","url":null,"abstract":"Background: With the increasing success of immune checkpoint blockades for cancer treatment, we increasingly need well-characterized preclinical models. Syngeneic mice models (with a fully competent immune system) have advantages that they are easily established and cost less, though they do not reflect genetic complexity of human tumors. We evaluated feasibility of syngeneic mice models of breast cancer by analyzing efficacy of immune checkpoint blockade and dynamic change of tumor immune microenvironment. Methods: We used syngeneic mice model of JC, 4T1, and EMT6 cells, which are all murine triple negative breast cancer in BALB/c mice. At the time when subcutaneous tumors reach at 50˜100mm^3, each mice models were divided into 2 groups for treatment versus no-treatment control. In the treatment group, mice version of anti-PD-1 antibody was intraperitoneally injected (q 3 days, x 6). Anti-tumor efficacy was monitored by measuring tumor volume. 9Tumor response9 was defined as a case with tumor volume less than that of control group by a standard error at a determined time point. Immune microenvironment was evaluated by measuring serum cytokines (IL-2, IL-6, IL-10, IFNγ, and TNFα) with legendplex and immune cells (CD3, CD4, CD8, CD56, and FOXP3) of peripheral blood with FACS before injection of PD-1 blockade, after 1st injection, and when euthanized. Tumor-infiltrating immune cells were evaluated with FACS, when euthanized. Results: The tumor response rate to PD-1 blockade was highest in the 4T1 model (54.5%, 6/11) compared to JC model (40%, 4/10) or EMT6 model (36.4%, 4/11). Bleeding 3 times and tumor obtainment when euthanized in each mouse were feasible for profiling of cytokines and immune cells. Although before treatment with PD-1 blockade, CD3+T cells in peripheral blood were slightly lower in 4T1 model (18.3±8.1%) than JC model (24.6±4.7%) or EMT6 model (27.9±6.3%), after injection of one dose of PD-1 blockade, CD3+T cells increased 1.5 times in 4T1 model (18.3% to 27.3%), whereas those CD3+T cells decreased slightly in JC model and EMT6 model. Dynamic changes were not observed in other subsets of peripheral immune cells in all 3 models. Serum TNFα (with statistical significance) and IFNγ (with borderline significance) were higher in responders than in non-responders or no-treatment control. Conclusions: Syngeneic mice models of breast cancer were feasible to investigate immune checkpoint blockades and monitor dynamic change of immune microenvironment. In this regard, such models may be used to evaluate immune checkpoint blockade-based combination therapy as well. Citation Format: Moon YW, Park N, Hur J, Pandey K, Cho YB, Kim SK, Lee SA, Son GW, Jo JM, An H-J. Feasibility of sygeneic mice models of breast cancer for research of immune checkpoint blockades [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-23.","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79247349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P6-21-03
M. Liu, K. Peng, M. Federspiel, S. Russell, B. Brunton, Yumei Zhou, N. Packiriswamy, J. Hubbard, C. Loprinzi, P. Peethambaram, K. Ruddy, J. Allred, E. Galanis, S. Okuno
Background: The live attenuated non-pathogenic Edmonston MV vaccine strain has advantages as an oncolytic platform given its tumor specificity, potent bystander effect, and ability to be engineered and retargeted. MV-NIS expresses the human thyroidal sodium-iodide symporter (NIS) and is selectively oncolytic, entering tumor cells through CD46 (overexpressed on many cancers, including breast cancer of all subtypes) and Nectin-4. NIS expression in MV-NIS infected cells permits noninvasive monitoring of virus spread by SPECT-CT imaging of Tc-99m pertechnetate or I-123 uptake. Methods: NCT01846091 is a standard 3+3 phase I trial of a single IT administration of MV-NIS in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) or metastatic breast cancer (MBC). Primary objectives are (a) safety and tolerability and (b) maximally tolerated single dose. The secondary clinical objective is to preliminarily assess antitumor efficacy at and away from the MV injection site. Key eligibility criteria were: absence of standard therapy with life prolonging intent; at least one lesion >1 cm amenable to percutaneous injection; and no impending visceral crisis. MV-NIS was administered on D1 with mandatory SPECT-CT at baseline (BL) and on D3D repeat SPECT-CT on D15D mandatory tumor biopsies on D3D optional tumor biopsies on D8D assessments for viremia and viral shedding at BL and on D3,D8,D15,D21; and standard imaging for restaging at BL,D21,W6,W12. Results: Accrual completed with 12 evaluable pts (6 SCCHN and 6 MBC) at 3 dose levels (10 8 , 3x10 8 , 10 9 TCID 50 ). The MBC group included 5 HR+/HER2- pts and 1 pt with mixed HR+/HER2- and HR+/HER2+ disease. 5 pts had evidence of disease progression prior to study participation. No dose limiting toxicities were observed among the MBC pts; AEs possibly related to MV-NIS in this group were gr2 fatigue, gr1 flu-like illness, gr2 lymphopenia (all n=1). No SCCHN responses were observed. Best response for the MBC pts was: stable disease (SD) >6 wks, n=4; clinical response, n=1; progression, n=1. One MBC pt with SD for 12 wks had positive SPECT/CT imaging at and away from the injection site on D3D she received additional doses at W9W 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-03.
{"title":"Abstract P6-21-03: Phase I trial of intratumoral (IT) administration of a NIS-expressing derivative manufactured from a genetically engineered strain of measles virus (MV)","authors":"M. Liu, K. Peng, M. Federspiel, S. Russell, B. Brunton, Yumei Zhou, N. Packiriswamy, J. Hubbard, C. Loprinzi, P. Peethambaram, K. Ruddy, J. Allred, E. Galanis, S. Okuno","doi":"10.1158/1538-7445.SABCS18-P6-21-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P6-21-03","url":null,"abstract":"Background: The live attenuated non-pathogenic Edmonston MV vaccine strain has advantages as an oncolytic platform given its tumor specificity, potent bystander effect, and ability to be engineered and retargeted. MV-NIS expresses the human thyroidal sodium-iodide symporter (NIS) and is selectively oncolytic, entering tumor cells through CD46 (overexpressed on many cancers, including breast cancer of all subtypes) and Nectin-4. NIS expression in MV-NIS infected cells permits noninvasive monitoring of virus spread by SPECT-CT imaging of Tc-99m pertechnetate or I-123 uptake. Methods: NCT01846091 is a standard 3+3 phase I trial of a single IT administration of MV-NIS in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) or metastatic breast cancer (MBC). Primary objectives are (a) safety and tolerability and (b) maximally tolerated single dose. The secondary clinical objective is to preliminarily assess antitumor efficacy at and away from the MV injection site. Key eligibility criteria were: absence of standard therapy with life prolonging intent; at least one lesion >1 cm amenable to percutaneous injection; and no impending visceral crisis. MV-NIS was administered on D1 with mandatory SPECT-CT at baseline (BL) and on D3D repeat SPECT-CT on D15D mandatory tumor biopsies on D3D optional tumor biopsies on D8D assessments for viremia and viral shedding at BL and on D3,D8,D15,D21; and standard imaging for restaging at BL,D21,W6,W12. Results: Accrual completed with 12 evaluable pts (6 SCCHN and 6 MBC) at 3 dose levels (10 8 , 3x10 8 , 10 9 TCID 50 ). The MBC group included 5 HR+/HER2- pts and 1 pt with mixed HR+/HER2- and HR+/HER2+ disease. 5 pts had evidence of disease progression prior to study participation. No dose limiting toxicities were observed among the MBC pts; AEs possibly related to MV-NIS in this group were gr2 fatigue, gr1 flu-like illness, gr2 lymphopenia (all n=1). No SCCHN responses were observed. Best response for the MBC pts was: stable disease (SD) >6 wks, n=4; clinical response, n=1; progression, n=1. One MBC pt with SD for 12 wks had positive SPECT/CT imaging at and away from the injection site on D3D she received additional doses at W9W 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-03.","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81810400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P5-12-04
B. Downs, L. Cope, M. Fackler, Soonweng Cho, A. Wolff, M. Regan, S. Sukumar, C. Umbricht
Background: Triple negative breast cancer (TNBC) accounts for 10-17% of all breast cancer and is more likely to be of higher histological grade, poorly differentiated, associated with a higher recurrence rate and with decreased overall survival. The clinical course of a TNBC patient remains difficult to predict, as tumors with homogenous morphological characteristics may vary in response to therapy and have divergent outcomes. Therefore, additional analytical methods are needed to better classify TNBC. Our goal is to refine the analysis of methylome datasets to derive reliable molecular signatures that can distinguish TNBC patients with good outcomes who may benefit from less aggressive treatment, from those with poor outcomes who would be candidates for more aggressive treatments. Methods: Our laboratory has conducted and reported, in this meeting, results from analysis of 450k methylation array data on a discovery set of 53 high-risk TNBC cases and 62 low-risk controls treated by locoregional therapy alone, as well as 5 normal breast tissue samples. High-risk cases were defined as patients that relapsed within 0.5 to 6.5 years from the time of diagnosis, while low-risk controls had no relapse and >4 year recurrence-free intervals (RFI). In this work, we devised and applied a novel methylation biomarker discovery program named Hypermethylated Outlier Detector (HOD) that emphasizes the selection of highly methylated markers in cases compared to controls, to find a high-risk signature in the TNBC discovery set. The methylation signature identified by HOD was interrogated in a test set of 50 TNBCs (with 16 recurrences) that did not receive chemotherapy, and in a second test set of 131 TNBCs (with 33 recurrences) that did receive chemotherapy. Results: HOD identified 39 hypermethylated markers (beta >0.20) that could accurately distinguish between the high-risk cases and the low-risk controls in the discovery set of TNBCs (n=115) treated with locoregional therapy alone. In the test set of TNBC (n=50) with no chemotherapy the 39 markers distinguished high from low risk individuals (likelihood ratio test P=0.049). In a second test set of TNBC (n=131) that received chemotherapy the 39 hypermethylated markers again distinguished high from low risk individuals (likelihood ratio test P=0.0043). Conclusions: We have presented evidence that a methylation signature identified by HOD can be used to identify TNBC patients that have a high-risk of relapse regardless of receiving chemotherapy. This methylation signature could potentially be used to inform physician decisions on therapeutic strategies for TNBC patients. This could ultimately lead to less aggressive treatment given to patients possessing a methylation profile consistent with a better prognosis. Conversely, patients with hypermethylation in the 39 markers will likely benefit from a more aggressive course of treatment. Citation Format: Downs BM, Cope LM, Fackler MJ, Cho S, Wolff AC, Regan MM, Sukuma
{"title":"Abstract P5-12-04: A new method of data analysis to derive DNA methylation signatures that stratify risk of recurrence in triple negative breast cancer","authors":"B. Downs, L. Cope, M. Fackler, Soonweng Cho, A. Wolff, M. Regan, S. Sukumar, C. Umbricht","doi":"10.1158/1538-7445.SABCS18-P5-12-04","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P5-12-04","url":null,"abstract":"Background: Triple negative breast cancer (TNBC) accounts for 10-17% of all breast cancer and is more likely to be of higher histological grade, poorly differentiated, associated with a higher recurrence rate and with decreased overall survival. The clinical course of a TNBC patient remains difficult to predict, as tumors with homogenous morphological characteristics may vary in response to therapy and have divergent outcomes. Therefore, additional analytical methods are needed to better classify TNBC. Our goal is to refine the analysis of methylome datasets to derive reliable molecular signatures that can distinguish TNBC patients with good outcomes who may benefit from less aggressive treatment, from those with poor outcomes who would be candidates for more aggressive treatments. Methods: Our laboratory has conducted and reported, in this meeting, results from analysis of 450k methylation array data on a discovery set of 53 high-risk TNBC cases and 62 low-risk controls treated by locoregional therapy alone, as well as 5 normal breast tissue samples. High-risk cases were defined as patients that relapsed within 0.5 to 6.5 years from the time of diagnosis, while low-risk controls had no relapse and >4 year recurrence-free intervals (RFI). In this work, we devised and applied a novel methylation biomarker discovery program named Hypermethylated Outlier Detector (HOD) that emphasizes the selection of highly methylated markers in cases compared to controls, to find a high-risk signature in the TNBC discovery set. The methylation signature identified by HOD was interrogated in a test set of 50 TNBCs (with 16 recurrences) that did not receive chemotherapy, and in a second test set of 131 TNBCs (with 33 recurrences) that did receive chemotherapy. Results: HOD identified 39 hypermethylated markers (beta >0.20) that could accurately distinguish between the high-risk cases and the low-risk controls in the discovery set of TNBCs (n=115) treated with locoregional therapy alone. In the test set of TNBC (n=50) with no chemotherapy the 39 markers distinguished high from low risk individuals (likelihood ratio test P=0.049). In a second test set of TNBC (n=131) that received chemotherapy the 39 hypermethylated markers again distinguished high from low risk individuals (likelihood ratio test P=0.0043). Conclusions: We have presented evidence that a methylation signature identified by HOD can be used to identify TNBC patients that have a high-risk of relapse regardless of receiving chemotherapy. This methylation signature could potentially be used to inform physician decisions on therapeutic strategies for TNBC patients. This could ultimately lead to less aggressive treatment given to patients possessing a methylation profile consistent with a better prognosis. Conversely, patients with hypermethylation in the 39 markers will likely benefit from a more aggressive course of treatment. Citation Format: Downs BM, Cope LM, Fackler MJ, Cho S, Wolff AC, Regan MM, Sukuma","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84215025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P2-09-16
Erika J. Crosby, W. Gwin, Serena Chang, H. Maecker, Veronica Lubkov, J. Snyder, G. Broadwater, T. Hyslop, T. Osada, A. Hobeika, Z. Hartman, M. Morse, H. Lyerly
Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2). Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy. Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies. Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.
{"title":"Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients","authors":"Erika J. Crosby, W. Gwin, Serena Chang, H. Maecker, Veronica Lubkov, J. Snyder, G. Broadwater, T. Hyslop, T. Osada, A. Hobeika, Z. Hartman, M. Morse, H. Lyerly","doi":"10.1158/1538-7445.SABCS18-P2-09-16","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P2-09-16","url":null,"abstract":"Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2). Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy. Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies. Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84386815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P3-10-07
S. Gampenrieder, R. Angela, G. Rinnerthaler, H. Hackl, M. Steiner, Walter Pulverer, A. Weinhaeusel, E. Klinglmayr, T. Karl, S. Ilic, C. Hufnagl, C. Hauser-kronberger, A. Egle, R. Greil
{"title":"Abstract P3-10-07: A 3-gene DNA methylation signature fails to predict response to bevacizumab in metastatic breast cancer patients treated within the TANIA phase III trial","authors":"S. Gampenrieder, R. Angela, G. Rinnerthaler, H. Hackl, M. Steiner, Walter Pulverer, A. Weinhaeusel, E. Klinglmayr, T. Karl, S. Ilic, C. Hufnagl, C. Hauser-kronberger, A. Egle, R. Greil","doi":"10.1158/1538-7445.SABCS18-P3-10-07","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P3-10-07","url":null,"abstract":"","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84894587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-P6-20-16
W. Tang, X. Huang, Z. Ou, H. Yan, J. Gan, Q. Dong, B. Tan, Y. Yang, Y. Guo, S. Li, B. Thomas, J-C. Yu
Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. These two characteristics make Trop-2 a potential drug target. An antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, has recently been demonstrated to be effective in treating triple negative breast cancer (TNBC) and gastric cancer patients. Here we present a Trop-2 ADC, BAT8003, which contains an uncleavable linker and a maytansine derivative as the payload. An A114C mutation on antibody heavy chain was introduced to BAT8003 for site-specific conjugation, in order to generate a more homogeneous product for a better pharmacokinetics profile. BAT8003 is also completely devoid of fucose modification, to allow for enhanced ADCC effect. We show that BAT8003 is effectively internalized upon binding to Trop-2, and inhibits proliferation of Trop2-overexpressed tumor cells with IC50s of ˜1 nM. In a TNBC (MDA-MB-468 cell) mouse xenograft model, BAT8003 strongly inhibits tumor growth at a dose level as low as 5 mg/kg. BAT8003 also demonstrates potent activity in another TNBC (MX-1 cell) mouse tumor model, in which it shows the same inhibition activity as the naked antibody conjugated heterogeneously with almost two fold payload (DAR 3.5), suggesting the effect caused by site-specific conjugation. We are currently developing BAT8003 for clinical evaluation in TNBC and other cancer indications. Citation Format: Tang W, Huang X, Ou Z, Yan H, Gan J, Dong Q, Tan B, Yang Y, Guo Y, Li S, Thomas B, Yu J-C. BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-16.
{"title":"Abstract P6-20-16: BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer","authors":"W. Tang, X. Huang, Z. Ou, H. Yan, J. Gan, Q. Dong, B. Tan, Y. Yang, Y. Guo, S. Li, B. Thomas, J-C. Yu","doi":"10.1158/1538-7445.SABCS18-P6-20-16","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-P6-20-16","url":null,"abstract":"Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. These two characteristics make Trop-2 a potential drug target. An antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, has recently been demonstrated to be effective in treating triple negative breast cancer (TNBC) and gastric cancer patients. Here we present a Trop-2 ADC, BAT8003, which contains an uncleavable linker and a maytansine derivative as the payload. An A114C mutation on antibody heavy chain was introduced to BAT8003 for site-specific conjugation, in order to generate a more homogeneous product for a better pharmacokinetics profile. BAT8003 is also completely devoid of fucose modification, to allow for enhanced ADCC effect. We show that BAT8003 is effectively internalized upon binding to Trop-2, and inhibits proliferation of Trop2-overexpressed tumor cells with IC50s of ˜1 nM. In a TNBC (MDA-MB-468 cell) mouse xenograft model, BAT8003 strongly inhibits tumor growth at a dose level as low as 5 mg/kg. BAT8003 also demonstrates potent activity in another TNBC (MX-1 cell) mouse tumor model, in which it shows the same inhibition activity as the naked antibody conjugated heterogeneously with almost two fold payload (DAR 3.5), suggesting the effect caused by site-specific conjugation. We are currently developing BAT8003 for clinical evaluation in TNBC and other cancer indications. Citation Format: Tang W, Huang X, Ou Z, Yan H, Gan J, Dong Q, Tan B, Yang Y, Guo Y, Li S, Thomas B, Yu J-C. BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-16.","PeriodicalId":20307,"journal":{"name":"Poster Session Abstracts","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84909571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：