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Abstract PD2-09: The role of CYP2D6 mediated tamoxifen metabolism in the suppression of ovarian function trial (SOFT) 摘要PD2-09: CYP2D6介导的他莫昔芬代谢在卵巢功能抑制中的作用试验(SOFT)
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.SABCS20-PD2-09
M. Goetz, G. Fleming, M. Kuffel, J. Hawse, J. Black, R. Weinshilboum, J. Ingle, P. Dell'Orto, O. Biasi, R. Kammler, S. Loi, M. Colleoni, G. Viale, P. Francis, M. Regan
Tamoxifen (T) is a pro-drug that undergoes CYP2D6-mediated metabolic activation to metabolites that more potently inhibit estrogen stimulated growth compared to the parent drug. While many studies have examined the role of CYP2D6 genotype in T-treated postmenopausal women, the role of CYP2D6 metabolism in premenopausal women (pre-MW) receiving T, with or without ovarian function suppression (OFS) or exemestane (E) and OFS is unknown. Methods: SOFT randomized 3066 (pre-MW) from 2003-2011 in 27 countries, stratified according to prior receipt or nonreceipt of chemotherapy and nodal status, to receive 5 years of T, T+OFS, or E+OFS. We designed a pharmacogenetics substudy (activated October 2010) to collect blood DNA from North American (NA) patients (pts) or to extract non-tumor DNA from available formalin fixed paraffin embedded (FFPE) tissue blocks. For pts with a blood sample, CYP2D6 was genotyped beginning with the Luminex Tag-It Mutation Detection Kit and when needed, with a copy number variation assay and/or sequencing assays. For pts with FFPE-derived DNA, CYP2D6 genotyping for *3, *4, *6, *9, *10, *17 and *41 was performed using a Taqman Allelic Discrimination Assay. CYP2D6 phenotypes were called by classifying pts on the basis of a combination of poor (PM: *3, *4, *5, *6, *7, *8), slow (SM: *10), intermediate (IM: *9, *17, *29, *41) and extensive metabolizer alleles (EM; all others). Activity scores (AS) from phenotypes assigned for each allele: 0 if PM, 0.25 if SM, 0.5 if IM and 1 if EM allele, and multiplied x2 or x3 if duplicate or triplicate. With concomitant use of potent CYP2D6 inhibitor, AS=0; use of weak inhibitor subtracted 0.5. Metabolizer status was defined by CYP2D6 genotype alone or in combination with CYP2D6 inhibitor use at randomization from the AS: extensive (AS 1.25 to 3), intermediate (AS >0.5 to 0.3 ng/ml in 1053, and successfully derived CYP2D6 genotypes for 765/3047 pts (25%). 182 (15%) pts had DFS events after 8 yrs median follow-up. Metabolizer status from genotype was 57% extensive, 29% intermediate, 15% slow/poor. Metabolizer status was not associated with DFS in pts assigned T alone (P=0.60; Table), nor in pts assigned T+OFS (P=0.41) or E+OFS (P=0.30). 11% of pts used CYP2D6 inhibitors concomitantly at randomization; for 8% it changed the metabolizer status. The results using this definition were consistent. Conclusion: This retrospective-prospective SOFT pharmacogenetics substudy found no relation of CYP2D6 metabolizer status with DFS in premenopausal pts receiving T, T + OFS, or E + OFS. Given that 50% were pretreated with chemotherapy, further study is needed regarding the role of CYP2D6 metabolism in patients treated with T monotherapy. Citation Format: Matthew P. Goetz, Gini F. Fleming, Mary Kuffel, John R. Hawse, John L. Black, Richard Weinshilboum, James N. Ingle, Patrizia dell’Orto, Olivia Biasi, Roswitha Kammler, Sherene Loi, Marco Colleoni, Giuseppe Viale, Prudence A Francis, Meredith M Regan. The role o
他莫昔芬(T)是一种前药,经过cyp2d6介导的代谢激活产生代谢物,与母体药物相比,更有效地抑制雌激素刺激的生长。虽然许多研究已经检查了CYP2D6基因型在接受T治疗的绝经后妇女中的作用,但CYP2D6代谢在接受T治疗的绝经前妇女(pre-MW)中,有或没有卵巢功能抑制(OFS)或依西美坦(E)和OFS的作用尚不清楚。方法:SOFT随机抽取来自27个国家2003-2011年的3066例(pre-MW)患者,根据既往接受或未接受化疗和淋巴结状态进行分层,接受5年的T、T+OFS或E+OFS治疗。我们设计了一项药物遗传学亚研究(2010年10月启动),从北美(NA)患者(pts)收集血液DNA,或从可用的福尔马林固定石蜡包埋(FFPE)组织块中提取非肿瘤DNA。对于有血液样本的患者,从Luminex Tag-It突变检测试剂盒开始进行CYP2D6基因分型,必要时进行拷贝数变异试验和/或测序试验。对于来自ffpe DNA的患者,采用Taqman等位基因区分法对*3、*4、*6、*9、*10、*17和*41进行CYP2D6基因分型。CYP2D6表型是根据不良(PM: *3、*4、*5、*6、*7、*8)、缓慢(SM: *10)、中间(IM: *9、*17、*29、*41)和广泛代谢等位基因(EM;所有人)。每个等位基因的表型活性评分(AS)为:PM为0,SM为0.25,IM为0.5,EM为1,重复或三次则乘以x2或x3。同时使用强效CYP2D6抑制剂,AS=0;使用弱抑制剂减去0.5。代谢状态由CYP2D6基因型单独或与CYP2D6抑制剂联合使用来定义,随机从AS:广泛(AS 1.25至3),中间(AS >0.5至0.3 ng/ml,在1053中,765/3047例(25%)成功衍生CYP2D6基因型。182(15%)名患者在中位随访8年后出现DFS事件。基因型代谢状态57%为广泛,29%为中等,15%为慢/差。在单独分配T治疗的患者中,代谢状态与DFS无关(P=0.60;T+OFS组(P=0.41)或E+OFS组(P=0.30)亦无差异。随机分组时,11%的患者同时使用CYP2D6抑制剂;对8%的人来说,它改变了代谢状态。使用这一定义的结果是一致的。结论:这项回顾性-前瞻性SOFT药物遗传学亚研究发现,在接受T、T + OFS或E + OFS治疗的绝经前患者中,CYP2D6代谢状态与DFS无关。考虑到50%的患者进行了化疗预处理,CYP2D6代谢在T单药治疗患者中的作用有待进一步研究。引文格式:Matthew P. Goetz, Gini F. Fleming, Mary Kuffel, John R. Hawse, John L. Black, Richard Weinshilboum, James N. Ingle, Patrizia dell 'Orto, Olivia Biasi, Roswitha Kammler, Sherene Loi, Marco Colleoni, Giuseppe Viale, Prudence A Francis, Meredith M Regan。CYP2D6介导的他莫昔芬代谢在抑制卵巢功能试验(SOFT)中的作用[摘要]。参见:2020年圣安东尼奥乳腺癌虚拟研讨会论文集;2020年12月8-11日;费城(PA): AACR;癌症杂志,2021;81(4增刊):摘要nr PD2-09。
{"title":"Abstract PD2-09: The role of CYP2D6 mediated tamoxifen metabolism in the suppression of ovarian function trial (SOFT)","authors":"M. Goetz, G. Fleming, M. Kuffel, J. Hawse, J. Black, R. Weinshilboum, J. Ingle, P. Dell'Orto, O. Biasi, R. Kammler, S. Loi, M. Colleoni, G. Viale, P. Francis, M. Regan","doi":"10.1158/1538-7445.SABCS20-PD2-09","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS20-PD2-09","url":null,"abstract":"Tamoxifen (T) is a pro-drug that undergoes CYP2D6-mediated metabolic activation to metabolites that more potently inhibit estrogen stimulated growth compared to the parent drug. While many studies have examined the role of CYP2D6 genotype in T-treated postmenopausal women, the role of CYP2D6 metabolism in premenopausal women (pre-MW) receiving T, with or without ovarian function suppression (OFS) or exemestane (E) and OFS is unknown. Methods: SOFT randomized 3066 (pre-MW) from 2003-2011 in 27 countries, stratified according to prior receipt or nonreceipt of chemotherapy and nodal status, to receive 5 years of T, T+OFS, or E+OFS. We designed a pharmacogenetics substudy (activated October 2010) to collect blood DNA from North American (NA) patients (pts) or to extract non-tumor DNA from available formalin fixed paraffin embedded (FFPE) tissue blocks. For pts with a blood sample, CYP2D6 was genotyped beginning with the Luminex Tag-It Mutation Detection Kit and when needed, with a copy number variation assay and/or sequencing assays. For pts with FFPE-derived DNA, CYP2D6 genotyping for *3, *4, *6, *9, *10, *17 and *41 was performed using a Taqman Allelic Discrimination Assay. CYP2D6 phenotypes were called by classifying pts on the basis of a combination of poor (PM: *3, *4, *5, *6, *7, *8), slow (SM: *10), intermediate (IM: *9, *17, *29, *41) and extensive metabolizer alleles (EM; all others). Activity scores (AS) from phenotypes assigned for each allele: 0 if PM, 0.25 if SM, 0.5 if IM and 1 if EM allele, and multiplied x2 or x3 if duplicate or triplicate. With concomitant use of potent CYP2D6 inhibitor, AS=0; use of weak inhibitor subtracted 0.5. Metabolizer status was defined by CYP2D6 genotype alone or in combination with CYP2D6 inhibitor use at randomization from the AS: extensive (AS 1.25 to 3), intermediate (AS >0.5 to 0.3 ng/ml in 1053, and successfully derived CYP2D6 genotypes for 765/3047 pts (25%). 182 (15%) pts had DFS events after 8 yrs median follow-up. Metabolizer status from genotype was 57% extensive, 29% intermediate, 15% slow/poor. Metabolizer status was not associated with DFS in pts assigned T alone (P=0.60; Table), nor in pts assigned T+OFS (P=0.41) or E+OFS (P=0.30). 11% of pts used CYP2D6 inhibitors concomitantly at randomization; for 8% it changed the metabolizer status. The results using this definition were consistent. Conclusion: This retrospective-prospective SOFT pharmacogenetics substudy found no relation of CYP2D6 metabolizer status with DFS in premenopausal pts receiving T, T + OFS, or E + OFS. Given that 50% were pretreated with chemotherapy, further study is needed regarding the role of CYP2D6 metabolism in patients treated with T monotherapy. Citation Format: Matthew P. Goetz, Gini F. Fleming, Mary Kuffel, John R. Hawse, John L. Black, Richard Weinshilboum, James N. Ingle, Patrizia dell’Orto, Olivia Biasi, Roswitha Kammler, Sherene Loi, Marco Colleoni, Giuseppe Viale, Prudence A Francis, Meredith M Regan. The role o","PeriodicalId":415047,"journal":{"name":"Poster Spotlight Session Abstracts","volume":"45 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123840040","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}
引用次数: 0
Abstract PD4-01: Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes : A multicenter randomized clinical trial. Sinodar One. 摘要PD4-01:一项多中心随机临床试验:T1-T2乳腺癌患者出现1-2个转移前哨淋巴结,与完全清扫相比,腋窝淋巴结保存。Sinodar。
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.sabcs20-pd4-01
C. Tinterri, E. Marrazzo, C. Anghelone, E. Barbieri, A. Sagona, A. Bottini, A. Rubino, D. Gentile, W. Gatzemeier, V. Errico, A. Testori, G. Canavese
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引用次数: 5
Abstract PD7-05: Neoadjuvant chemotherapy selectively alters spatially-defined immune landscapes in clinical luminal B HR+/HER2- breast cancers: Analysis of the breast cancer genome guided therapy study (BEAUTY) 摘要PD7-05:新辅助化疗选择性地改变临床腔内B HR+/HER2-乳腺癌的空间定义免疫景观:乳腺癌基因组引导治疗研究分析(BEAUTY)
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.SABCS20-PD7-05
J. Carter, J. Boughey, Jun He, V. Suman, Xue Wang, J. Kachergus, Krishna R. Kalari, Liewei Wang, R. Weinshilboum, A. Moyer, S. Mclaughlin, A. Moreno-Aspitia, D. Northfelt, R. Gray, J. Ingle, E. Thompson, M. Goetz
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引用次数: 2
Abstract PD8-03: A FOXA1/FRA1-centered transcriptional axis regulates interferon signaling in high FOXA1-associated endocrine-resistant and metastatic breast cancer 以FOXA1/ fra1为中心的转录轴在FOXA1相关的内分泌抵抗和转移性乳腺癌中调节干扰素信号
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.SABCS20-PD8-03
Xiaoyong Fu, Resel Pereira, L. Qin, C. Angelis, Sarmistha Nanda, M. Shea, A. Nardone, R. Jeselsohn, Ofir Cohen, N. Wagle, M. Rimawi, C. Osborne, R. Schiff
{"title":"Abstract PD8-03: A FOXA1/FRA1-centered transcriptional axis regulates interferon signaling in high FOXA1-associated endocrine-resistant and metastatic breast cancer","authors":"Xiaoyong Fu, Resel Pereira, L. Qin, C. Angelis, Sarmistha Nanda, M. Shea, A. Nardone, R. Jeselsohn, Ofir Cohen, N. Wagle, M. Rimawi, C. Osborne, R. Schiff","doi":"10.1158/1538-7445.SABCS20-PD8-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS20-PD8-03","url":null,"abstract":"","PeriodicalId":415047,"journal":{"name":"Poster Spotlight Session Abstracts","volume":"144 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127488333","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}
引用次数: 1
Abstract PD11-09: Vadis trial: Phase II trial of nelipepimut-s peptide vaccine in women with DCIS of the breast 摘要PD11-09: Vadis试验:nelipepimut-s肽疫苗在乳腺DCIS女性中的II期试验
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.sabcs20-pd11-09
A. O'Shea, G. Clifton, N. Qiao, B. Heckman-Stoddard, M. Wojtowicz, E. Dimond, I. Bedrosian, D. Weber, Alexander Husband, R. Pastorello, L. Vornik, G. Peoples, E. Mittendorf
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引用次数: 0
Abstract PD12-12: Floor and ceiling effects in the EORTC QLQ-C30 physical functioning subscale among patients with breast cancer enrolled in commercial clinical trials vs. a community trial PD12-12:参与商业临床试验的乳腺癌患者与社区试验的EORTC QLQ-C30身体功能亚量表的下限和上限效应
Pub Date : 2021-02-15 DOI: 10.1158/1538-7445.SABCS20-PD12-12
M. Murugappan, B. King-Kallimanis, Christina Mangir, Lyn Howie, V. Bhatnagar, J. Beaver, E. Basch, P. Kluetz
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引用次数: 0
Abstract PD3-09: Sulindac reduces breast density and alters collagen alignment in patients on aromatase inhibitors 摘要PD3-09:舒林达克降低乳腺密度,改变芳香酶抑制剂患者的胶原排列
Pub Date : 2020-02-15 DOI: 10.1158/1538-7445.sabcs19-pd3-09
P. Thompson, Chuan Huang, B. Wertheim, C. Preece, Jie Yang, Jessica A. Martinez, D. Roe, P. Chalasani, A. Stopeck
Background. Preclinical and observational evidence supports cancer prevention activity of non-steroidal anti-inflammatory drugs (NSAIDs) in the breast via suppression of prostaglandin E2 (PGE2) synthesis by cyclooxygenase-2 (COX2). Evidence includes linking of PGE2 to aromatase activity and estrogen synthesis in breast adipose tissue, as well as effects on collagen and breast density (BD). Methods. In an open-label trial, we evaluated the effect of the non-selective NSAID sulindac at 150 mg bid for 12 months on BD in 52 postmenopausal women taking adjuvant aromatase inhibitors (AIs) for breast cancer. BD was measured using a fat-water decomposition MRI based BD measure (MRD) previously shown to be more quantitative than mammographic density. A non-randomized observation cohort of 46 postmenopausal women on AI without NSAID use was conducted in parallel to assess the effect of AI on MRD over 12 months. Eligible participants were recruited at two study sites and included women with an intact, unaffected contralateral breast and BI-RADS ≥ 2. Each subject’s MRI_BD measures at baseline and at 6 and 12 months were included in linear mixed models for longitudinal data. Log-transformation was applied to the outcome of BD. Covariates included log-transformed baseline BD, time on AI, and baseline body mass index (BMI) and change in BMI. Breast tissue collagen fiber alignment for 30 women with paired breast biopsies, before and after 6 months on sulindac, was examined using Second-Harmonic Generation (SHG) microscopy and analysis of the distribution (histogram) of ‘straight’ fibers in three randomly selected areas of breast tissue. Straightness of individual fibers was calculated as the linear length of a fiber divided by the distance along the fiber. Results. Participants on sulindac intervention had a significant change in BD relative to baseline BD at 6 (p=0.05) and 12 months (p Citation Format: Patricia Thompson, Chuan Huang, Betsy Wertheim, Christina Preece, Jie Yang, Jessica Martinez, Denise Roe, Pavani Chalasani, Alison Stopeck. Sulindac reduces breast density and alters collagen alignment in patients on aromatase inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-09.
背景。临床前和观察性证据支持非甾体抗炎药(NSAIDs)通过抑制环氧化酶-2 (COX2)合成前列腺素E2 (PGE2)在乳腺中的预防癌症活性。证据包括PGE2与乳腺脂肪组织中芳香酶活性和雌激素合成的联系,以及对胶原蛋白和乳腺密度(BD)的影响。方法。在一项开放标签试验中,我们评估了52名服用辅助芳香酶抑制剂(AIs)治疗乳腺癌的绝经后妇女服用非选择性非甾体抗炎药舒林酸(150mg / bid, 12个月)对BD的影响。采用基于脂肪-水分解MRI的BD测量(MRD)测量BD,先前显示比乳房x线摄影密度更定量。对46名未使用非甾体抗炎药的绝经后妇女进行了一项非随机队列观察,以评估AI对MRD在12个月内的影响。在两个研究地点招募了符合条件的参与者,包括对侧乳房完整、未受影响且BI-RADS≥2的女性。每个受试者在基线、6个月和12个月时的MRI_BD测量包括在纵向数据的线性混合模型中。将对数变换应用于BD的结果。协变量包括对数变换后的基线BD、人工智能治疗时间、基线体重指数(BMI)和BMI变化。在使用舒林达克6个月前后,对30名接受配对乳房活检的女性进行乳房组织胶原纤维排列,使用二次谐波生成(SHG)显微镜检查,并分析三个随机选择的乳房组织区域的“直”纤维分布(直方图)。单个纤维的直线度计算为纤维的线长除以沿纤维的距离。结果。舒林达干预组患者在6个月和12个月时的BD与基线相比有显著变化(p=0.05) (p来源:Patricia Thompson, Chuan Huang, Betsy Wertheim, Christina Preece, Jie Yang, Jessica Martinez, Denise Roe, Pavani Chalasani, Alison Stopeck)。舒林达克降低乳腺密度,改变芳香酶抑制剂患者的胶原排列[摘要]。摘自:2019年圣安东尼奥乳腺癌研讨会论文集;2019年12月10日至14日;费城(PA): AACR;中国癌症杂志,2020;20(4):1 - 9。
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引用次数: 0
Abstract PD7-05: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer 摘要PD7-05:一项评估口服选择性雌激素受体降解剂(SERD) GDC-9545在绝经后雌激素受体阳性(ER+) HER2阴性(HER2-)转移性乳腺癌患者中的作用的首次人体I期研究
Pub Date : 2020-02-14 DOI: 10.1158/1538-7445.sabcs19-pd7-05
K. Jhaveri, E. Winer, E. Lim, Jose AlejandroPerez Fidalgo, M. Bellet, I. Mayer, V. Boni, J. Patel, A. Bardia, Jose M Garcia, P. Kabos, Mary Gates, Ya-Chi Chen, J. Fredrickson, Xiaojing Wang, L. Friedman, J. Spoerke, S. Gendreau, Ciara Metcalfe, Lichuan Liu, Ching-Wei Chang, S. Monemi, Monica Gonzalez, U. McCurry, S. Milan, E. Humke, S. Loi
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引用次数: 7
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