Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-pd9-07
G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge, R. Jeselsohn
Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q<0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p<0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p<0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p<0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p<0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q < 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q<0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q<0.05) and higher MAPK activation score (-0.81 vs -1.19, q<0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 sig
背景：浸润性小叶癌（ILC）是第二常见的乳腺癌（BC）亚型，占病例的15%。虽然已经描述了ILC和浸润性无特殊类型癌（NST）之间的一些生物学差异，但大多数数据来自原发肿瘤。相比之下，转移性ILC的生物学仍然不明确。本研究旨在利用多组学方法研究转移性ILC的独特基因组学、转录组学和免疫景观。方法：这项现实世界的研究包括确诊的NST或纯ILC患者，他们在已知的转移性疾病背景下进行了转移灶活检或乳房病变。肿瘤进行全外显子组测序（NGS 592, NextSeq； WES, NovaSeq），全转录组测序（WTS, NovaSeq） （Caris Life Sciences, Phoenix， AZ）。比较不同组织学亚型的人口学特征和基线分子特征。NGS评估肿瘤突变负荷（TMB；高≥10 mut/MB）。通过RNAseq反褶积（quanTIseq）估计免疫细胞群。通过GSEA进行途径富集分析。总生存期（OS）的定义从活检日期到任何原因导致的死亡，使用Kaplan-Meier估计。统计学检验采用卡方和Mann-Whitney U，多重检验校正（q<0.05）。结果：在2651例转移性BC样本（ILC n = 608; NST n = 2043）中，ILC患者年龄较大（中位年龄67岁vs中位年龄63岁），且更可能是白人（ILC为81.5% vs NST为73.1%），均为p&；lt;0.05。通过IHC， ILC中HR+/HER2-（83.6%比55.9%）较多，三阴性（11.9%比29.8%）或HER2+（4.6%比14.3%）较少，p < 0.05。PAM50亚型在ILC和NST之间存在差异：luminal A (Lum A)（31.1%比13.7%）和luminal B (Lum B)（44.9%比43.8%）内在亚型在ILC中富集，而NST更常见的是基础亚型（1.2%比22.4%）和her2富集（19.8%比22.2%），均为p amp；lt;0.05。在luminal BC中，Lum B在两种组织学中都比Lum A更常见，但Lum A在ILC中比例更高（ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B）， p amp;lt;0.0001。比较多组学分析集中于922例HR+/HER2-肿瘤（ILC n = 275; NST n = 647）。与NST相比，ILC的CDH1（87.3%比6.1%）、PIK3CA（52.7%比38.5%）、FOXA1（9.0%比3.4%）、ERBB2（7.1%比2.0%）、ARID1A和NF1（均为q&；lt;0.05）突变频率更高，TMB高（17.7%比9.9%），但TP53（15.7%比33.3%）、ESR1（10.9%比18.1%）和GATA3（2.3%比14.9%）突变频率较低，FGFR1扩增（15.3%比6.7%）均为q&；lt;0.05。ILC具有较高的雄激素受体表达（91.2% vs 83.5%, q<0.05）和较高的MAPK激活评分（-0.81 vs -1.19, q<0.05），符合腔内激素驱动的表型。NST肿瘤显示了参与细胞周期和代谢活性的途径的富集，包括E2F靶点、G2M检查点、MYC靶点、mTORC1信号传导、糖酵解和未折叠蛋白反应（NES: 1.5-2.7, FDR<0.25）。ILC肿瘤中B细胞、树突状细胞、中性粒细胞、NK细胞和M2巨噬细胞的浸润率较高，M1巨噬细胞浸润率较低，差异均为0.05。ILC免疫检查点基因差异表达(上调：CD274 （PD-L1）、PDCD1 （PD-1）、TNFSF14、CEACAM1、CD160，折叠变化（FC）： 1.2-1.5；down: HAVCR2 (TIM-3): FC: 1.2)，所有q&；lt;0.05。腔内ILC和NST的中位OS （mOS）相似（33.8个月vs 35.4个月）；Hr 1.0, 95% ci 0.91-1.3)。Lum A ILC和NST之间没有mOS差异（47.4 vs 50.5 mo; HR 1.0, 0.84-1.43），而Lum B ILC的mOS比NST差（27.4 vs 35.3 mo; HR 1.3, 1.1-1.6）。结论：该研究代表了迄今为止最大的转移性ILC多组学特征队列，揭示了与NST相比不同的基因组，转录组学和免疫特征。这些发现突出了ILC的独特生物学特性，并可能为未来的亚型特异性治疗策略提供信息。引用格式：G. Nader-Marta， S. Kumar Deshmukh， K. Fanucci， P. Tarantino， S. Schnitt， A. Lee， S. Oesterreich， S. Wu， J. Xiu， P. Advani， M. Lustberg， N. Lin， S. Tolaney， E. Mayer， O. Metzger， G. Sledge Jr， R. Jeselsohn。转移性小叶性乳腺癌的基因组学、转录组学和免疫特征[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PD9-07。
{"title":"Abstract PD9-07: The Genomic, Transcriptomic, and Immune Hallmarks of Metastatic Lobular Breast Cancer","authors":"G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge, R. Jeselsohn","doi":"10.1158/1557-3265.sabcs25-pd9-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-pd9-07","url":null,"abstract":"Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q&lt;0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p&lt;0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p&lt;0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p&lt;0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p&lt;0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q &lt; 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q&lt;0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q&lt;0.05) and higher MAPK activation score (-0.81 vs -1.19, q&lt;0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 sig","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps5-02-12
Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia
Background: Trastuzumab deruxtecan (T-DXd), a novel antibody-drug conjugate (ADC), has shown promising intracranial efficacy in breast cancer (BC) patients with brain metastases (BM). This meta-analysis evaluates the intracranial activity and systemic efficacy of T-DXd in patients with metastatic BC and BM. Methods: A systematic search was conducted from inception until May 6, 2025, across PubMed, Cochrane Library, and oncology conference abstracts (ASCO, ESMO, SABCS, and EANO). Eligible studies included clinical trials and cohort studies reporting outcomes for BC patients with BM receiving T-DXd. Random-effects meta-analysis models with Freeman-Tukey transformations were used for pooling proportions (intracranial clinical benefit rate [IC-CBR], intracranial objective response rate [IC-ORR], and 12-month systemic overall survival [OS]). Systemic progression-free survival (PFS) was pooled using a random-effects inverse-variance model. For PFS, means and standard deviations (SDs) were extracted when available or estimated from medians and IQRs using the Wan et al. (2014) method: mean = (Q1 + median + Q3)/3 and SD = (Q3 − Q1)/1.35, adjusted for sample size. Heterogeneity was assessed using the I2 statistic, with values ≤25% considered low, 26-75% moderate, and >75% high. Registration: osf.io/swghm. Results: Of the 489 screened records, 14 studies were included; 1 was a randomized controlled trial, 6 were prospective single-arm trials, and 7 were retrospective cohort studies, including real-world data from early access programs. Median patient age was 56.3 years; 97.3% had HER2-positive BC, and 2.7% HER2-low. Prior cranial radiotherapy was administered in 61%, with concurrent radiotherapy at T-DXd initiation in 1.4%. Median follow-up duration was 12.9 months (IQR: 11-15). T-DXd was administered uniformly at 5.4 mg/kg IV every three weeks, with protocol-specified dose reductions allowed. Pooled IC-CBR was 81% (95% CI: 69-91%, p<0.001), indicating strong intracranial clinical efficacy, with low heterogeneity (I2=18.6%). IC-ORR was 62% (95% CI: 51-74%, p<0.001), suggestive of substantial intracranial tumor responses. Moderate heterogeneity was noted (I2=71.8%). The pooled mean systemic PFS was 12.6 months (95% CI: 7.1-18.1, I2=99.8%, p<0.001). Pooled 12-month OS was 81% (95% CI: 66-93%, p<0.001), highlighting favorable survival outcomes despite high heterogeneity (I2=86.5%). Conclusion: T-DXd demonstrates robust intracranial activity and 12-month survival in breast cancer patients with brain metastases. The pooled IC-CBR of 81% notably exceeds historical benchmarks reported with T-DM1 or chemotherapy, which typically range from 30-50% in this population. Prospective studies are needed to refine patient selection and optimize therapeutic sequencing. Citation Format: Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia. Intracranial A
背景：曲妥珠单抗德鲁西替康（T-DXd）是一种新型抗体-药物偶联物（ADC），在乳腺癌（BC）脑转移（BM）患者中显示出有希望的颅内疗效。这项荟萃分析评估了T-DXd在转移性BC和BM患者中的颅内活动和全身疗效。方法：系统检索从研究开始到2025年5月6日，检索对象包括PubMed、Cochrane图书馆和肿瘤学会议摘要（ASCO、ESMO、SABCS和EANO）。符合条件的研究包括报告接受T-DXd治疗的BC患者预后的临床试验和队列研究。采用Freeman-Tukey转换的随机效应荟萃分析模型进行合并比例（颅内临床获益率[IC-CBR]、颅内客观缓解率[IC-ORR]和12个月全身总生存率[OS]）。系统无进展生存期（PFS）采用随机效应反方差模型进行汇总。对于PFS，使用Wan等人（2014）的方法提取可用的平均值和标准差（SD），或从中位数和iqr中估计：平均值= (Q1 +中位数+ Q3)/3, SD = (Q3−Q1)/1.35，根据样本量进行调整。使用I2统计量评估异质性，值≤25%为低，26-75%为中等，>；高75%。注册:osf.io / swghm。结果：在筛选的489份记录中，纳入了14项研究；1项是随机对照试验，6项是前瞻性单臂试验，7项是回顾性队列研究，包括来自早期准入项目的真实数据。患者年龄中位数为56.3岁；97.3%为her2阳性，2.7%为her2低。61%的患者先前进行了头部放疗，1.4%的患者在T-DXd开始时同时进行了放疗。中位随访时间为12.9个月（IQR: 11-15）。T-DXd每三周以5.4 mg/kg IV的剂量均匀给药，允许方案规定的剂量减少。综合IC-CBR为81% (95% CI: 69-91%, p<0.001)，颅内临床疗效强，异质性低（I2=18.6%）。IC-ORR为62% (95% CI: 51-74%, p<0.001)，提示颅内肿瘤有实质性反应。中度异质性（I2=71.8%）。合并平均系统PFS为12.6个月（95% CI: 7.1-18.1, I2=99.8%, p<0.001）。12个月的总OS为81% (95% CI: 66-93%, p<0.001)，尽管异质性很高（I2=86.5%），但仍显示出良好的生存结果。结论：T-DXd在乳腺癌脑转移患者中表现出强劲的颅内活性和12个月的生存率。81%的总IC-CBR明显超过了T-DM1或化疗的历史基准，在该人群中通常在30-50%之间。需要前瞻性研究来完善患者选择和优化治疗顺序。引文格式：Z. Sarfraz， V. Podder， K. Vazquez， F. Akkoc Mustafayev， M. Jaramillo， K. A. Qidwai， M. Ganiyani， V. Andion Camargo， R. Mahtani， M. Ahluwalia。曲妥珠单抗德鲁司替康治疗乳腺癌脑转移患者的颅内活动及全身疗效[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS5-02-12。
{"title":"Abstract PS5-02-12: Intracranial Activity and Systemic Efficacy of Trastuzumab Deruxtecan in Breast Cancer Patients with Brain Metastases","authors":"Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia","doi":"10.1158/1557-3265.sabcs25-ps5-02-12","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-02-12","url":null,"abstract":"Background: Trastuzumab deruxtecan (T-DXd), a novel antibody-drug conjugate (ADC), has shown promising intracranial efficacy in breast cancer (BC) patients with brain metastases (BM). This meta-analysis evaluates the intracranial activity and systemic efficacy of T-DXd in patients with metastatic BC and BM. Methods: A systematic search was conducted from inception until May 6, 2025, across PubMed, Cochrane Library, and oncology conference abstracts (ASCO, ESMO, SABCS, and EANO). Eligible studies included clinical trials and cohort studies reporting outcomes for BC patients with BM receiving T-DXd. Random-effects meta-analysis models with Freeman-Tukey transformations were used for pooling proportions (intracranial clinical benefit rate [IC-CBR], intracranial objective response rate [IC-ORR], and 12-month systemic overall survival [OS]). Systemic progression-free survival (PFS) was pooled using a random-effects inverse-variance model. For PFS, means and standard deviations (SDs) were extracted when available or estimated from medians and IQRs using the Wan et al. (2014) method: mean = (Q1 + median + Q3)/3 and SD = (Q3 − Q1)/1.35, adjusted for sample size. Heterogeneity was assessed using the I2 statistic, with values ≤25% considered low, 26-75% moderate, and &gt;75% high. Registration: osf.io/swghm. Results: Of the 489 screened records, 14 studies were included; 1 was a randomized controlled trial, 6 were prospective single-arm trials, and 7 were retrospective cohort studies, including real-world data from early access programs. Median patient age was 56.3 years; 97.3% had HER2-positive BC, and 2.7% HER2-low. Prior cranial radiotherapy was administered in 61%, with concurrent radiotherapy at T-DXd initiation in 1.4%. Median follow-up duration was 12.9 months (IQR: 11-15). T-DXd was administered uniformly at 5.4 mg/kg IV every three weeks, with protocol-specified dose reductions allowed. Pooled IC-CBR was 81% (95% CI: 69-91%, p&lt;0.001), indicating strong intracranial clinical efficacy, with low heterogeneity (I2=18.6%). IC-ORR was 62% (95% CI: 51-74%, p&lt;0.001), suggestive of substantial intracranial tumor responses. Moderate heterogeneity was noted (I2=71.8%). The pooled mean systemic PFS was 12.6 months (95% CI: 7.1-18.1, I2=99.8%, p&lt;0.001). Pooled 12-month OS was 81% (95% CI: 66-93%, p&lt;0.001), highlighting favorable survival outcomes despite high heterogeneity (I2=86.5%). Conclusion: T-DXd demonstrates robust intracranial activity and 12-month survival in breast cancer patients with brain metastases. The pooled IC-CBR of 81% notably exceeds historical benchmarks reported with T-DM1 or chemotherapy, which typically range from 30-50% in this population. Prospective studies are needed to refine patient selection and optimize therapeutic sequencing. Citation Format: Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia. Intracranial A","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps5-08-07
A. Kahn, J. Du, N. Casasanta, S. Schellhorn, M. Digiovanna, T. Sanft, M. Rozenblit, A. Silber, L. Pusztai, Z. Rahman, D. O'Neil, R. Legare, W. Kidwai, J. Kanowitz, A. Bulgaru, N. Fischbach, S. Hall, K. Fenn, K. Blenman, O. Blaha, E. Winer, I. Krop, D. Rimm, M. Lustberg
Background: Trastuzumab-deruxtecan (T-DXd) showed impressive efficacy in patients whose breast cancers are either human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) positive or HER2-low/ultralow. In a phase 2 trial, patients with HER2-IHC 0 who received T-DXd had an objective response rate of approximately 30%, revealing activity regardless of HER2-IHC status. In this study, we will treat patients with advanced HER2 IHC 0 breast cancers with T-DXd and assess biomarkers of response and resistance to therapy. We will investigate patients’ tumor biopsies for more precise quantitative HER2 tests, including the High-Sensitivity (HS)-HER2 Troplex testing, that could help determine if T-DXd is active in patients with HER2-IHC 0 tumors regardless of HER2 quantitative expression or if there is a potentially optimal cutoff value of HER2 expression with respect to clinical outcomes for response, improving patient selection and prevention of unnecessary toxicity. Methods: This is a non-randomized, single-arm, open-label, phase 2 study to assess the efficacy and safety of T-DXd in patients whose breast cancer is HER2-IHC 0 (including 0-null and 0-ultralow) in all prior biopsies, with unresectable and/or metastatic disease regardless of hormone receptor (HR) status (NCT06750484). Key eligibility criteria include ECOG-PS 0-2; up to 2 prior lines of systemic cytotoxic therapy for treatment in the metastatic setting; no upper limit of prior endocrine, immunologic or targeted therapy lines. Fifty subjects will be included to achieve 82% power to detect a difference in ORR of 0.15 from historical control (ORR in experimental arm of 0.3 vs. ORR in historical control of 0.15) using a two-sided exact test with a target significance level of 0.1. The study treatment with T-DXd administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight will be continued in the absence of withdrawal of subject consent, progressive disease (PD), death, or unacceptable toxicity. Patients will be followed and evaluated by RECIST v1.1 criteria. Objective response to T-DXd will be evaluated in the entire study population and separately in the High-Sensitivity (HS)-HER2 Troplex detectable and non-detectable cohorts (defined by the limit of detection [LOD] of the analytic HS-HER2 Troplex assay). In addition, HER2 tissue concentrations (measured by the HS-HER2 Troplex assay in attomole/mm2) will be plotted and analyzed as a function of response to determine levels of tumor expression and potential cut-points associated with benefit from T-DXd. Since the Troplex assay simultaneously provides TROP2 levels in attomole/mm2, the influence of TROP2 levels on response to T-DXd will also be exploratorily investigated. Additional objectives are to assess efficacy in terms of progression-free survival and overall survival, safety, and explore potential biomarkers of response and resistance to therapy with T-DXd. The trial is currently open and enrollin
背景：曲妥珠单抗-德鲁西替康（T-DXd）对人表皮生长因子受体2 （HER2）免疫组化（IHC）阳性或HER2低/超低的乳腺癌患者显示出令人印象深刻的疗效。在一项2期试验中，接受T-DXd治疗的HER2-IHC 0患者的客观缓解率约为30%，显示出与HER2-IHC状态无关的活性。在这项研究中，我们将用T-DXd治疗晚期HER2 IHC 0乳腺癌患者，并评估对治疗的反应和耐药的生物标志物。我们将对患者的肿瘤活检进行更精确的HER2定量检测，包括高灵敏度(HS)-HER2 Troplex检测，这可以帮助确定T-DXd在HER2- ihc 0肿瘤患者中是否有活性，而不考虑HER2的定量表达，或者HER2表达是否存在潜在的最佳临界值，这与临床结果的反应、改善患者选择和预防不必要的毒性有关。方法：这是一项非随机、单臂、开放标签的2期研究，旨在评估T-DXd在所有既往活检中HER2-IHC为0（包括0-null和0-超低）、不可切除和/或转移性疾病的乳腺癌患者中的疗效和安全性，无论激素受体（HR）状态如何（NCT06750484）。主要资格标准包括ECOG-PS 0-2；对于转移性肿瘤患者，既往接受最多2次全身性细胞毒治疗；先前的内分泌、免疫或靶向治疗线没有上限。将纳入50名受试者，使用目标显著性水平为0.1的双侧精确检验，以达到82%的能力来检测与历史对照组的ORR差异为0.15（实验组的ORR为0.3，历史对照组的ORR为0.15）。在没有受试者同意退出、疾病进展、死亡或不可接受的毒性的情况下，T-DXd每3周静脉注射5.4 mg / kg体重的研究治疗将继续进行。患者将按照RECIST v1.1标准进行随访和评估。对T-DXd的客观反应将在整个研究人群中进行评估，并分别在高灵敏度(HS)-HER2 Troplex可检测和不可检测队列中进行评估（由HS-HER2 Troplex分析的检测限[LOD]定义）。此外，将绘制和分析HER2组织浓度（通过HS-HER2 Troplex测定，单位为attomole/mm2）作为应答的函数，以确定肿瘤表达水平和与T-DXd获益相关的潜在切割点。由于Troplex试验同时提供了以原子摩尔/mm2为单位的TROP2水平，因此TROP2水平对T-DXd应答的影响也将进行探索性研究。其他目标是评估无进展生存期和总生存期、安全性方面的有效性，并探索对T-DXd治疗的反应和耐药的潜在生物标志物。该试验目前正在开放并招募患者。引文格式：A. Kahn， J. Du， N. Casasanta， S. Schellhorn， M. Digiovanna， T. Sanft， M. Rozenblit， A. Silber， L. Pusztai， Z. Rahman， D. O'Neil， R. Legare， W. Kidwai， J. Kanowitz， A. Bulgaru， N. Fischbach， S. Hall， K. Fenn， K. Blenman， O. Blaha， E. Winer， I. Krop， D. Rimm， M. Lustberg。曲妥珠单抗Deruxtecan在先前治疗的HER2免疫组织化学（IHC） 0晚期乳腺癌- HER2范式试验中的开放标签单臂2期试验[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS5-08-07。
{"title":"Abstract PS5-08-07: Open-label Single-arm Phase 2 Trial of Trastuzumab Deruxtecan in Previously Treated HER2-Immunohistochemistry (IHC) 0 Advanced Breast Cancer - HER2 PARADIGM trial","authors":"A. Kahn, J. Du, N. Casasanta, S. Schellhorn, M. Digiovanna, T. Sanft, M. Rozenblit, A. Silber, L. Pusztai, Z. Rahman, D. O'Neil, R. Legare, W. Kidwai, J. Kanowitz, A. Bulgaru, N. Fischbach, S. Hall, K. Fenn, K. Blenman, O. Blaha, E. Winer, I. Krop, D. Rimm, M. Lustberg","doi":"10.1158/1557-3265.sabcs25-ps5-08-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-08-07","url":null,"abstract":"Background: Trastuzumab-deruxtecan (T-DXd) showed impressive efficacy in patients whose breast cancers are either human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) positive or HER2-low/ultralow. In a phase 2 trial, patients with HER2-IHC 0 who received T-DXd had an objective response rate of approximately 30%, revealing activity regardless of HER2-IHC status. In this study, we will treat patients with advanced HER2 IHC 0 breast cancers with T-DXd and assess biomarkers of response and resistance to therapy. We will investigate patients’ tumor biopsies for more precise quantitative HER2 tests, including the High-Sensitivity (HS)-HER2 Troplex testing, that could help determine if T-DXd is active in patients with HER2-IHC 0 tumors regardless of HER2 quantitative expression or if there is a potentially optimal cutoff value of HER2 expression with respect to clinical outcomes for response, improving patient selection and prevention of unnecessary toxicity. Methods: This is a non-randomized, single-arm, open-label, phase 2 study to assess the efficacy and safety of T-DXd in patients whose breast cancer is HER2-IHC 0 (including 0-null and 0-ultralow) in all prior biopsies, with unresectable and/or metastatic disease regardless of hormone receptor (HR) status (NCT06750484). Key eligibility criteria include ECOG-PS 0-2; up to 2 prior lines of systemic cytotoxic therapy for treatment in the metastatic setting; no upper limit of prior endocrine, immunologic or targeted therapy lines. Fifty subjects will be included to achieve 82% power to detect a difference in ORR of 0.15 from historical control (ORR in experimental arm of 0.3 vs. ORR in historical control of 0.15) using a two-sided exact test with a target significance level of 0.1. The study treatment with T-DXd administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight will be continued in the absence of withdrawal of subject consent, progressive disease (PD), death, or unacceptable toxicity. Patients will be followed and evaluated by RECIST v1.1 criteria. Objective response to T-DXd will be evaluated in the entire study population and separately in the High-Sensitivity (HS)-HER2 Troplex detectable and non-detectable cohorts (defined by the limit of detection [LOD] of the analytic HS-HER2 Troplex assay). In addition, HER2 tissue concentrations (measured by the HS-HER2 Troplex assay in attomole/mm2) will be plotted and analyzed as a function of response to determine levels of tumor expression and potential cut-points associated with benefit from T-DXd. Since the Troplex assay simultaneously provides TROP2 levels in attomole/mm2, the influence of TROP2 levels on response to T-DXd will also be exploratorily investigated. Additional objectives are to assess efficacy in terms of progression-free survival and overall survival, safety, and explore potential biomarkers of response and resistance to therapy with T-DXd. The trial is currently open and enrollin","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps2-06-19
L. B. Amin, C. Shaefer, G. Cecilia, D. Allen-Benson, E. Caballero, M. Chavez-MacGregor
Background: Early-stage breast cancer is typically treated with a multi-modality approach. Among older patients, concerns exist about suboptimal cancer care delivery and the possibility of greater risk of experiencing treatment delays. Since treatment delays are associated with adverse outcomes, we sought to describe patterns of care among older patients with breast cancer in Texas and estimate delays in chemotherapy administration. Methods: Using Medicare Fee-For-Service parts A, B, and D claims data, we identified individuals in Texas who underwent unilateral or bilateral mastectomy or lumpectomy from 2017 through 2020, had a breast cancer diagnosis code and had 1 year of continuous enrollment before and after surgery. Individuals with metastatic disease and malignancies of non-breast origin were excluded. Using CPT, HCPCS, and NDC codes, we developed an algorithm to identify breast cancer subtype according to treatment received. A total of 5,988 patients were identified and categorized. Among the 1,562 patients treated with chemotherapy the number of days from diagnosis to first dose of chemotherapy was estimated for patients receiving neoadjuvant chemotherapy and the number of days between surgery to chemotherapy for those treated in the adjuvant setting. Treatment delay was defined as >60 days. Descriptive statistics were reported and logistic regression models were performed to predict the odds of delaying chemotherapy. Results: Of the 5,988 individuals identified with early-stage breast cancer (HR-positive 81.5%, TNBC 11.4, HER2-positive 7.1%), median age was 72 years old [QR 69-77]. Majority (91.8%) were White and 17.6% resided in rural counties. Among those receiving chemotherapy, 32.3% received it in the neoadjuvant setting (35.9% TNBC, 34.6% HER2-positive, and 22.9% HR-positive). The median time from diagnosis to neoadjuvant chemotherapy was 34 days. For patients that received adjuvant chemotherapy, the median number of days from surgery to first dose of chemotherapy was 48 days. Overall, 24.8% of patients receiving chemotherapy experienced a delay. Among patients who received neoadjuvant chemotherapy, those living in counties with higher high-school graduation rates were significantly less likely to have a chemotherapy delay (OR=0.41, 95%CI 0.19-0.87), more comorbidities (OR=1.19 95%CI 0.99-1.41) had a borderline association with more delays. For those who received adjuvant chemotherapy, older age (OR=1.2, 95%CI 1.04-1.38), and receiving MammaPrint or Oncotype testing (OR=1.71, 95%CI 1.24-2.36), was associated with a higher likelihood of chemotherapy delay. Estimates for patients treated for TNBC and HER2-positive breast cancer suggested a lower likelihood of experiencing delays compared to those with HR-positive tumors. Conclusions: Among older individuals with early-stage breast cancer enrolled in Medicare Fee-For-Service in Texas, 24.8% of patients receiving chemotherapy experienced a delay > 60 days from either diagn
背景：早期乳腺癌通常采用多模式治疗。在老年患者中，存在着对不理想的癌症护理提供和经历治疗延误的更大风险的担忧。由于治疗延迟与不良结果相关，我们试图描述德克萨斯州老年乳腺癌患者的护理模式，并估计化疗给药的延迟。方法：使用医疗保险按服务收费部分A、B和D索赔数据，我们确定了2017年至2020年期间在德克萨斯州接受单侧或双侧乳房切除术或乳房肿瘤切除术的个体，这些个体具有乳腺癌诊断代码，并且在手术前后连续登记1年。有转移性疾病和非乳腺来源恶性肿瘤的个体被排除在外。使用CPT、HCPCS和NDC代码，我们开发了一种算法，根据所接受的治疗来识别乳腺癌亚型。共有5988名患者被确定并分类。在1,562例接受化疗的患者中，估计接受新辅助化疗的患者从诊断到第一次化疗的天数，以及接受辅助治疗的患者从手术到化疗的天数。治疗延迟定义为&；gt；60天。报告了描述性统计和逻辑回归模型来预测延迟化疗的几率。结果：5988例早期乳腺癌患者（hr阳性81.5%，TNBC阳性11.4，her2阳性7.1%）中位年龄为72岁[QR 69-77]。大多数（91.8%）是白人，17.6%居住在农村县。在接受化疗的患者中，32.3%在新辅助环境下接受化疗（TNBC患者占35.9%，her2阳性患者占34.6%，hr阳性患者占22.9%）。从诊断到新辅助化疗的中位时间为34天。对于接受辅助化疗的患者，从手术到第一次化疗的中位天数为48天。总体而言，接受化疗的患者中有24.8%经历了延迟。在接受新辅助化疗的患者中，生活在高中毕业率较高的县的患者化疗延迟的可能性显着降低（OR=0.41, 95%CI 0.19-0.87），更多的合合症（OR=1.19 95%CI 0.99-1.41）与更多的延迟有边缘关联。对于接受辅助化疗的患者，年龄较大（OR=1.2, 95%CI 1.04-1.38）和接受MammaPrint或Oncotype检测（OR=1.71, 95%CI 1.24-2.36）与化疗延迟的可能性较高相关。对TNBC和her2阳性乳腺癌患者的估计表明，与hr阳性肿瘤患者相比，TNBC和her2阳性乳腺癌患者出现延迟的可能性较低。结论：在德克萨斯州的老年早期乳腺癌患者中，接受化疗的患者中有24.8%的患者延迟接受化疗。从诊断到化疗或手术到化疗的60天。了解老年患者的护理模式可以为治疗模式提供重要的见解，并确定易受伤害的患者。引用格式：L. B. Amin， C. Shaefer， G. Cecilia， D. Allen-Benson， E. Caballero， M. Chavez-MacGregor。早期乳腺癌的治疗趋势：一项基于德克萨斯州医疗保险按服务收费参保者的人群研究[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS2-06-19。
{"title":"Abstract PS2-06-19: Treatment Trends in Early-Stage Breast Cancer: A Population-Based Study of Medicare Fee-For-Service Enrollees in Texas","authors":"L. B. Amin, C. Shaefer, G. Cecilia, D. Allen-Benson, E. Caballero, M. Chavez-MacGregor","doi":"10.1158/1557-3265.sabcs25-ps2-06-19","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-06-19","url":null,"abstract":"Background: Early-stage breast cancer is typically treated with a multi-modality approach. Among older patients, concerns exist about suboptimal cancer care delivery and the possibility of greater risk of experiencing treatment delays. Since treatment delays are associated with adverse outcomes, we sought to describe patterns of care among older patients with breast cancer in Texas and estimate delays in chemotherapy administration. Methods: Using Medicare Fee-For-Service parts A, B, and D claims data, we identified individuals in Texas who underwent unilateral or bilateral mastectomy or lumpectomy from 2017 through 2020, had a breast cancer diagnosis code and had 1 year of continuous enrollment before and after surgery. Individuals with metastatic disease and malignancies of non-breast origin were excluded. Using CPT, HCPCS, and NDC codes, we developed an algorithm to identify breast cancer subtype according to treatment received. A total of 5,988 patients were identified and categorized. Among the 1,562 patients treated with chemotherapy the number of days from diagnosis to first dose of chemotherapy was estimated for patients receiving neoadjuvant chemotherapy and the number of days between surgery to chemotherapy for those treated in the adjuvant setting. Treatment delay was defined as &gt;60 days. Descriptive statistics were reported and logistic regression models were performed to predict the odds of delaying chemotherapy. Results: Of the 5,988 individuals identified with early-stage breast cancer (HR-positive 81.5%, TNBC 11.4, HER2-positive 7.1%), median age was 72 years old [QR 69-77]. Majority (91.8%) were White and 17.6% resided in rural counties. Among those receiving chemotherapy, 32.3% received it in the neoadjuvant setting (35.9% TNBC, 34.6% HER2-positive, and 22.9% HR-positive). The median time from diagnosis to neoadjuvant chemotherapy was 34 days. For patients that received adjuvant chemotherapy, the median number of days from surgery to first dose of chemotherapy was 48 days. Overall, 24.8% of patients receiving chemotherapy experienced a delay. Among patients who received neoadjuvant chemotherapy, those living in counties with higher high-school graduation rates were significantly less likely to have a chemotherapy delay (OR=0.41, 95%CI 0.19-0.87), more comorbidities (OR=1.19 95%CI 0.99-1.41) had a borderline association with more delays. For those who received adjuvant chemotherapy, older age (OR=1.2, 95%CI 1.04-1.38), and receiving MammaPrint or Oncotype testing (OR=1.71, 95%CI 1.24-2.36), was associated with a higher likelihood of chemotherapy delay. Estimates for patients treated for TNBC and HER2-positive breast cancer suggested a lower likelihood of experiencing delays compared to those with HR-positive tumors. Conclusions: Among older individuals with early-stage breast cancer enrolled in Medicare Fee-For-Service in Texas, 24.8% of patients receiving chemotherapy experienced a delay &gt; 60 days from either diagn","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"122 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1078-0432.ccr-25-3447
Ben Tran, Mark Voskoboynik, Sang-We Kim, Charlotte Lemech, Enric Carcereny, Sun Young Rha, Myung-Ju Ahn, Enriqueta Felip, Ki Hyeong Lee, Eduardo Castañón Álvarez, James Chih-Hsin. Yang, Paolo Antonio. Ascierto, Mariano Provencio Pulla, Shunsuke Kondo, Yasutoshi Kuboki, Daniel Freeman, Xuyang Song, Jorge Blando, Steven Eck, Florian J. Song, Zoey Tang, Michael Kuziora, Shelby D. Gainer, Patrick Mitchell, Julie Asare, Amal Ayyoub, Ikbel Achour, Deepa S. Subramaniam, Seock-Ah Im
Purpose: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on PD-1-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-human study (NCT03530397) is to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and antitumor activity of volrustomig. This manuscript reports findings for the dose-exploration and immunotherapy-naïve expansion cohorts. Patients and Methods:Patients aged ≥18 years who had histologically or cytologically confirmed advanced cancer, measurable disease, performance status of 0–1, and adequate organ and marrow function received volrustomig 2.25–2500 mg intravenously every 3 weeks until confirmed disease progression, initiation of alternative cancer therapy, unacceptable toxicity, or consent withdrawal. The primary objective in the dose-exploration phase was to evaluate the safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included assessment of preliminary antitumor activity and volrustomig pharmacokinetics. Results:86 patients received volrustomig treatment in the dose-exploration and immunotherapy-naïve expansion cohorts; 78 (90.7%) patients were immunotherapy-naïve. Common treatment-related adverse events (TRAEs) were pruritus (30.2%), hypothyroidism (26.7%), hyperthyroidism (24.4%), and rash (24.4%). TRAEs led to treatment discontinuation in 33.7% of patients and one death. At doses ≥500 mg, volrustomig demonstrated robust peripheral and intra-tumoral T cell activation and proliferation at levels greater than those seen with approved PD-1/CTLA-4 regimens. Seventeen (19.8%) patients had objective responses, including 2 (2.3%) complete responses; median response duration was 17.5 months. Conclusions: These results support further development of volrustomig as monotherapy and in combination regimens, with phase 3 trials ongoing.
{"title":"Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy from a first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody","authors":"Ben Tran, Mark Voskoboynik, Sang-We Kim, Charlotte Lemech, Enric Carcereny, Sun Young Rha, Myung-Ju Ahn, Enriqueta Felip, Ki Hyeong Lee, Eduardo Castañón Álvarez, James Chih-Hsin. Yang, Paolo Antonio. Ascierto, Mariano Provencio Pulla, Shunsuke Kondo, Yasutoshi Kuboki, Daniel Freeman, Xuyang Song, Jorge Blando, Steven Eck, Florian J. Song, Zoey Tang, Michael Kuziora, Shelby D. Gainer, Patrick Mitchell, Julie Asare, Amal Ayyoub, Ikbel Achour, Deepa S. Subramaniam, Seock-Ah Im","doi":"10.1158/1078-0432.ccr-25-3447","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3447","url":null,"abstract":"Purpose: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on PD-1-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-human study (NCT03530397) is to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and antitumor activity of volrustomig. This manuscript reports findings for the dose-exploration and immunotherapy-naïve expansion cohorts. Patients and Methods:Patients aged ≥18 years who had histologically or cytologically confirmed advanced cancer, measurable disease, performance status of 0–1, and adequate organ and marrow function received volrustomig 2.25–2500 mg intravenously every 3 weeks until confirmed disease progression, initiation of alternative cancer therapy, unacceptable toxicity, or consent withdrawal. The primary objective in the dose-exploration phase was to evaluate the safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included assessment of preliminary antitumor activity and volrustomig pharmacokinetics. Results:86 patients received volrustomig treatment in the dose-exploration and immunotherapy-naïve expansion cohorts; 78 (90.7%) patients were immunotherapy-naïve. Common treatment-related adverse events (TRAEs) were pruritus (30.2%), hypothyroidism (26.7%), hyperthyroidism (24.4%), and rash (24.4%). TRAEs led to treatment discontinuation in 33.7% of patients and one death. At doses ≥500 mg, volrustomig demonstrated robust peripheral and intra-tumoral T cell activation and proliferation at levels greater than those seen with approved PD-1/CTLA-4 regimens. Seventeen (19.8%) patients had objective responses, including 2 (2.3%) complete responses; median response duration was 17.5 months. Conclusions: These results support further development of volrustomig as monotherapy and in combination regimens, with phase 3 trials ongoing.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps4-09-17
D. Gilbert, A. Thakur, T. Tabernacki, M. Loria, M. A. Mart, S. Rhodes, S. Gupta, K. Mishra, M. McNamara
Background: Current breast cancer (BCa) screening guidelines do not adequately address transgender populations, despite known differences in hormone exposure and post-operative anatomy between transgender and cisgender patients of the same gender. The effects of gender-affirming hormone therapy (HT) and surgical intervention (SX) on BCa risk in transgender individuals remain poorly understood. Objective: To evaluate the incidence and predictors of BCa in transgender men and women, stratified by gender-affirming interventions (HT and SX). Methods: Using TriNetX (TriNetX, Inc., Cambridge, MA, United States), a de-identified health research network, we identified adults with a diagnosis of Gender Identity Disorder (GID) (ICD-10: F64.x) from 2003-2023. Patients were divided by sex assigned at birth and categorized into cohorts based on gender-affirming intervention: no intervention (NI), HT alone (≥1 year), and HT with SX. SX was limited to top surgeries, such as breast contouring and mastectomies. Patients with a past history of BCa, bottom surgery, or inconsistent medical timelines were excluded. The primary outcome was a diagnosis of malignant neoplasm of the breast (ICD-10: C50.x), recorded in at least two instances. Logistic regression was used to identify predictors of BCa risk. Results: Among 33,775 transgender women (assigned male at birth), 12 (0.036%) were diagnosed with BCa. Of these, 83.3% had no intervention, 16.7% received HT, and none received both HT and SX. HT alone was not associated with increased risk of developing BCa. Independent predictors of BCa included age at GID diagnosis (OR =d 1.07 per year, 95% CI: 1.05-1.09, p < 0.001) and Black race (OR = 2.71, 95% CI: 1.13-5.76, p = 0.015). Among 44,117 transgender men (assigned female at birth), 37 (0.084%) were diagnosed with BCa. Most cases occurred in those with no intervention (72.9%), followed by HT+SX (21.6%), and HT alone (5.4%). Hormone therapy alone was not associated with increased risk. Individuals who received both HT and SX had significantly higher BCa prevalence compared to those with HT alone (0.25% vs. 0.07%, p = 0.01). Multivariate analysis showed increased odds of BCa with combined HT and SX (OR = 3.62, 95% CI: 1.02-10.14, p = 0.024), Black race (OR = 3.35, 95% CI: 1.20-8.15, p = 0.012), and age at GID diagnosis (OR = 1.07 per year, 95% CI: 1.05-1.09, p < 0.001). Conclusion: This is the largest cohort study to date assessing BCa risk among transgender patients, and the first study to stratify risk by level of gender-affirming intervention. HT alone does not appear to increase BCa risk in transgender individuals. However, among transgender men, the combination of HT and SX was associated with significantly elevated risk. These findings may reflect differences in tissue preservation during mastectomy, lower screening rates, or increased pathological surveillance post-surgery. Black race and age at GID diagnosis were also associated with greater risk amon
背景：目前的乳腺癌（BCa）筛查指南没有充分考虑跨性别人群，尽管已知跨性别和同性顺性患者在激素暴露和术后解剖结构方面存在差异。性别确认激素治疗（HT）和手术干预（SX）对跨性别者BCa风险的影响尚不清楚。目的：通过性别确认干预（HT和SX）进行分层，评估跨性别男性和女性BCa的发病率和预测因素。方法：使用TriNetX (TriNetX, Inc., Cambridge， MA, United States)，一个去身份化的健康研究网络，我们确定了诊断为性别认同障碍（GID） （ICD-10: F64）的成年人。X) 2003-2023年。患者按出生时的性别划分，并根据性别确认干预分为：不干预（NI）、单独HT（≥1年）和HT联合SX。SX仅限于顶级手术，如乳房轮廓和乳房切除术。既往有BCa病史、底部手术或不一致的医疗时间表的患者被排除在外。主要结果是诊断为乳腺恶性肿瘤（ICD-10: C50）。X)，记录至少两个实例。采用Logistic回归确定BCa风险的预测因素。结果：在33,775名变性女性（出生时为男性）中，12名（0.036%）被诊断为BCa。其中，83.3%未进行干预，16.7%接受了激素治疗，没有人同时接受了激素治疗和SX治疗。单纯HT与BCa发病风险增加无关。BCa的独立预测因子包括GID诊断时的年龄（OR = 1.07 /年，95% CI: 1.05-1.09, p < 0.001）和黑人种族（OR = 2.71, 95% CI: 1.13-5.76, p = 0.015）。在44117名跨性别男性（出生时被指定为女性）中，37名（0.084%）被诊断为BCa。未进行干预的病例最多（72.9%），其次是HT+SX（21.6%）和单纯HT（5.4%）。单独的激素治疗与风险增加无关。同时接受HT和SX治疗的患者BCa患病率明显高于单独接受HT治疗的患者（0.25% vs 0.07%, p = 0.01）。多因素分析显示，BCa合并HT和SX （OR = 3.62, 95% CI: 1.02-10.14, p = 0.024）、黑人（OR = 3.35, 95% CI: 1.20-8.15, p = 0.012）和GID诊断年龄（OR = 1.07 /年，95% CI: 1.05-1.09, p < 0.001）的几率增加。结论：这是迄今为止评估跨性别患者BCa风险的最大队列研究，也是第一个根据性别肯定干预水平对风险进行分层的研究。单独的HT似乎不会增加跨性别者的BCa风险。然而，在跨性别男性中，HT和SX的组合与风险显著升高相关。这些发现可能反映了乳房切除术期间组织保存的差异，较低的筛查率或术后病理监测的增加。黑人种族和性别认知障碍症诊断时的年龄也与跨性别男性和女性患性别认知障碍症的风险增加有关。我们的研究结果强调了修订BCa筛查指南的必要性，以反映跨性别人群独特的风险概况，并解决护理中的交叉差异。引用格式：D. Gilbert， A. Thakur， T. Tabernacki， M. Loria， M. A. Mart， S. Rhodes， S. Gupta， K. Mishra， M. McNamara。内科和外科干预后变性人乳腺癌的发生[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS4-09-17。
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Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps5-04-04
S. Preston, S. Ryan, D. Speakman
Background: BREASTEST Plus is a novel blood-based diagnostic assay used alongside imaging to support breast cancer screening decision-making. While prior validation studies have demonstrated the analytical and clinical performance of the assay, real-world evidence (RWE) on its clinical utility and long-term impact on patient outcomes remains essential. To address this, BCAL Diagnostics has initiated a prospective, observational registry study aimed at evaluating how BREASTEST Plus influences physician decision-making and patient outcomes in routine clinical practice. Methods: This multi-centre, prospective registry will enroll a minimum of 2,000 women across Australia who undergo BREASTEST Plus testing as part of their clinical assessment. Inclusion criteria are broad, reflecting routine clinical use, and will include both symptomatic and asymptomatic women aged ≥30 years. Treating clinicians will complete a structured decision-impact survey following receipt of results to assess how the assay influenced diagnostic or management decisions. Patients will be followed for up to five years, with key endpoints including one and two year sensitivity and specificity. Results: Primary endpoints are: (1) proportion of cases in which BREASTEST Plus results changed clinical management, and (2) concordance of assay results with cancer diagnoses over time. Secondary endpoints include reduction in unnecessary procedures, and patient-reported metrics. Interim analyses will be performed at 12-month intervals to inform clinical and regulatory stakeholders. Conclusion: This RWE registry is the first of its kind for a lipid-based breast cancer diagnostic and will provide critical insights into the utility, impact, and long-term value of BREASTEST Plus in everyday practice. Results will inform guidelines, reimbursement decisions, and broader adoption strategies across healthcare systems. Citation Format: S. Preston, S. Ryan, D. Speakman. Design of a Prospective Registry Study to Evaluate the Decision Impact and Clinical Utility of the Lipidomic-based Blood Test BREASTEST Plus in Breast Cancer Screening [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS5-04-04.
背景：BREASTEST Plus是一种新的基于血液的诊断方法，与影像学一起使用，以支持乳腺癌筛查决策。虽然先前的验证研究已经证明了该检测的分析和临床性能，但其临床实用性和对患者预后的长期影响的真实证据（RWE）仍然是必不可少的。为了解决这个问题，BCAL诊断公司发起了一项前瞻性、观察性注册研究，旨在评估breast - est Plus在常规临床实践中如何影响医生决策和患者预后。方法：这个多中心的前瞻性注册将在澳大利亚招募至少2000名接受BREASTEST Plus测试作为临床评估一部分的妇女。纳入标准广泛，反映常规临床使用，并将包括年龄≥30岁的有症状和无症状妇女。治疗临床医生将在收到结果后完成一项结构化的决策影响调查，以评估该检测方法如何影响诊断或管理决策。患者将被随访长达5年，关键终点包括1年和2年的敏感性和特异性。结果：主要终点是：(1)breast - est Plus结果改变临床管理的病例比例，(2)随着时间的推移，检测结果与癌症诊断的一致性。次要终点包括减少不必要的手术和患者报告的指标。中期分析将每隔12个月进行一次，以告知临床和监管利益相关者。结论：这个RWE注册表是第一个基于脂质的乳腺癌诊断，将为日常实践中BREASTEST Plus的效用、影响和长期价值提供关键见解。结果将为指导方针、报销决策和更广泛的医疗保健系统采用策略提供信息。引文格式：S. Preston， S. Ryan， D. Speakman。一项前瞻性注册研究的设计，以评估基于脂质组学的血液检测BREASTEST Plus在乳腺癌筛查中的决策影响和临床应用。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS5-04-04。
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Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps2-03-09
A. Dominique Nascimento Lima, A. Mattar, F. Pimentel Cavalcante, F. Pereira Zerwes, M. Antonini, M. Leite Kraft, A. Oliveira de Alencar, A. de Queiroz Germano, D. Pitanga Torres, E. Goulart Carneiro, C. Freitas de Lima, R. Zocchio Torresan, F. Palermo Brenelli, M. Lichtenfels, A. Frasson, J. Bines, E. Camargo Millen
Background: Neoadjuvant chemotherapy (NAC) has become a cornerstone in breast cancer treatment, especially for locally advanced tumors and aggressive subtypes such as triple-negative and HER2-positive disease. NAC can reduce tumor size, increase breast-conserving surgery (BCS) eligibility, improve cosmetic outcomes, and allow early systemic control. However, concerns persist regarding whether BCS following NAC achieves oncologic outcomes comparable to those of BCS followed by adjuvant chemotherapy (AC). This study aimed to compare long-term survival outcomes in patients undergoing BCS after NAC versus AC in a real-world Brazilian cohort. Methods: We conducted a retrospective, multicenter cohort study across six Brazilian institutions (five private, one public). Women aged 18 years or older with clinical stage 0-III breast cancer who underwent BCS (either standard lumpectomy or therapeutic mammoplasty) between 2016 and 2022 were included. Patients were divided into two groups according to whether they received NAC or AC. Data on demographics, tumor characteristics, and treatments were collected from institutional registries. The outcomes assessed were locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), progression-free survival (PFS), and overall survival (OS). Survival outcomes were estimated using Kaplan-Meier methods, and Cox proportional hazards models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs). This study was approved by the IDOR Ethics Committee (reference 6,907,736). Results: A total of 268 women underwent breast-conserving surgery; 138 (51.5%) received NAC and 130 (48.5%) received AC. The mean age of the cohort was 53.1 years (SD 12.1), with patients in the NAC group being slightly younger (mean 51.1 vs. 55.2 years). Over half of the patients (56.8%) were over 50 years old, and 51.1% identified as white. Invasive ductal carcinoma was the predominant histological type (84.7%), and the majority of patients (73.8%) presented with early-stage disease (≤ stage IIA). Most underwent lumpectomy (72.4%), while 27.6% had therapeutic mammoplasty. In the NAC group, 57.2% had tumors classified as stage >IIB. After a median follow-up of 60 months, no statistically significant differences were observed in survival outcomes between the NAC and AC groups. The hazard ratio for LRRFS was 1.29 (95% CI: 0.28-5.88; p=0.816), for BCSS was 0.52 (95% CI: 0.10-2.61; p=0.473), for DRFS was 1.05 (95% CI: 0.31-3.52; p=0.955), for PFS was 1.19 (95% CI: 0.36-3.96; p=0.869), and for OS was 0.73 (95% CI: 0.18-2.91; p=0.710). Conclusion: In this multicenter Brazilian cohort, breast-conserving surgery following neoadjuvant chemotherapy was associated with survival outcomes comparable to those of surgery followed by adjuvant chemotherapy. These findings support the oncologic safety of BCS after NAC and reinforce its role as a safe and effective option in the ind
背景：新辅助化疗（NAC）已成为乳腺癌治疗的基石，特别是对于局部晚期肿瘤和侵袭性亚型，如三阴性和her2阳性疾病。NAC可以减小肿瘤大小，增加保乳手术（BCS）的资格，改善美容效果，并允许早期全身控制。然而，人们仍然担心NAC后BCS是否能达到与辅助性化疗（AC）后BCS相比的肿瘤预后。本研究旨在比较巴西现实世界队列中NAC和AC术后BCS患者的长期生存结果。方法：我们在6家巴西机构（5家私立机构，1家公立机构）进行了一项回顾性、多中心队列研究。在2016年至2022年期间接受BCS（标准乳房肿瘤切除术或治疗性乳房成形术）的18岁或以上临床0-III期乳腺癌妇女被纳入研究。根据患者是否接受了NAC或AC，将患者分为两组。人口统计学、肿瘤特征和治疗数据从机构登记处收集。评估的结果包括局部无复发生存期（LRRFS）、远处无复发生存期（DRFS）、乳腺癌特异性生存期（BCSS）、无进展生存期（PFS）和总生存期（OS）。使用Kaplan-Meier方法估计生存结果，并使用Cox比例风险模型评估风险比（hr）和95%置信区间（ci）。本研究获得IDOR伦理委员会批准（参考文献6,907,736）。结果：共有268名妇女接受了保乳手术；138例（51.5%）接受NAC治疗，130例（48.5%）接受AC治疗。该队列的平均年龄为53.1岁（SD 12.1）， NAC组患者稍年轻（平均51.1岁对55.2岁）。超过一半的患者（56.8%）年龄在50岁以上，51.1%为白人。浸润性导管癌是主要的组织学类型（84.7%），大多数患者（73.8%）表现为早期（≤IIA期）。大多数患者行乳房肿瘤切除术（72.4%），而27.6%的患者行治疗性乳房成形术。在NAC组中，57.2%的肿瘤分期为IIB期。中位随访60个月后，NAC组和AC组的生存结果无统计学差异。LRRFS的风险比为1.29 (95% CI: 0.28-5.88; p=0.816)， BCSS的风险比为0.52 (95% CI: 0.10-2.61; p=0.473)， DRFS的风险比为1.05 (95% CI: 0.31-3.52; p=0.955)， PFS的风险比为1.19 (95% CI: 0.36-3.96; p=0.869)， OS的风险比为0.73 （95% CI: 0.18-2.91; p=0.710）。结论：在这个多中心的巴西队列中，新辅助化疗后的保乳手术与手术后辅助化疗的生存结果相当。这些发现支持了NAC后BCS的肿瘤学安全性，并加强了其作为乳腺癌个体化手术治疗安全有效选择的作用。引文格式：A. Dominique Nascimento Lima， A. Mattar， F. Pimentel Cavalcante， F. Pereira Zerwes， M. Antonini， M. Leite Kraft， A. Oliveira de Alencar， A. de Queiroz Germano， D. Pitanga Torres， E. Goulart Carneiro， C. Freitas de Lima， R. Zocchio Torresan， F. Palermo Brenelli， M. Lichtenfels， A. Frasson， J. Bines， E. Camargo Millen。新辅助化疗后进行保乳手术安全吗？巴西多中心队列研究[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS2-03-09。
{"title":"Abstract PS2-03-09: Is it safe to offer breast-conserving surgery after neoadjuvant chemotherapy? A Brazilian multicenter cohort study","authors":"A. Dominique Nascimento Lima, A. Mattar, F. Pimentel Cavalcante, F. Pereira Zerwes, M. Antonini, M. Leite Kraft, A. Oliveira de Alencar, A. de Queiroz Germano, D. Pitanga Torres, E. Goulart Carneiro, C. Freitas de Lima, R. Zocchio Torresan, F. Palermo Brenelli, M. Lichtenfels, A. Frasson, J. Bines, E. Camargo Millen","doi":"10.1158/1557-3265.sabcs25-ps2-03-09","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-03-09","url":null,"abstract":"Background: Neoadjuvant chemotherapy (NAC) has become a cornerstone in breast cancer treatment, especially for locally advanced tumors and aggressive subtypes such as triple-negative and HER2-positive disease. NAC can reduce tumor size, increase breast-conserving surgery (BCS) eligibility, improve cosmetic outcomes, and allow early systemic control. However, concerns persist regarding whether BCS following NAC achieves oncologic outcomes comparable to those of BCS followed by adjuvant chemotherapy (AC). This study aimed to compare long-term survival outcomes in patients undergoing BCS after NAC versus AC in a real-world Brazilian cohort. Methods: We conducted a retrospective, multicenter cohort study across six Brazilian institutions (five private, one public). Women aged 18 years or older with clinical stage 0-III breast cancer who underwent BCS (either standard lumpectomy or therapeutic mammoplasty) between 2016 and 2022 were included. Patients were divided into two groups according to whether they received NAC or AC. Data on demographics, tumor characteristics, and treatments were collected from institutional registries. The outcomes assessed were locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), progression-free survival (PFS), and overall survival (OS). Survival outcomes were estimated using Kaplan-Meier methods, and Cox proportional hazards models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs). This study was approved by the IDOR Ethics Committee (reference 6,907,736). Results: A total of 268 women underwent breast-conserving surgery; 138 (51.5%) received NAC and 130 (48.5%) received AC. The mean age of the cohort was 53.1 years (SD 12.1), with patients in the NAC group being slightly younger (mean 51.1 vs. 55.2 years). Over half of the patients (56.8%) were over 50 years old, and 51.1% identified as white. Invasive ductal carcinoma was the predominant histological type (84.7%), and the majority of patients (73.8%) presented with early-stage disease (≤ stage IIA). Most underwent lumpectomy (72.4%), while 27.6% had therapeutic mammoplasty. In the NAC group, 57.2% had tumors classified as stage &gt;IIB. After a median follow-up of 60 months, no statistically significant differences were observed in survival outcomes between the NAC and AC groups. The hazard ratio for LRRFS was 1.29 (95% CI: 0.28-5.88; p=0.816), for BCSS was 0.52 (95% CI: 0.10-2.61; p=0.473), for DRFS was 1.05 (95% CI: 0.31-3.52; p=0.955), for PFS was 1.19 (95% CI: 0.36-3.96; p=0.869), and for OS was 0.73 (95% CI: 0.18-2.91; p=0.710). Conclusion: In this multicenter Brazilian cohort, breast-conserving surgery following neoadjuvant chemotherapy was associated with survival outcomes comparable to those of surgery followed by adjuvant chemotherapy. These findings support the oncologic safety of BCS after NAC and reinforce its role as a safe and effective option in the ind","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"94 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps3-12-29
B. Wu, W. Thant, E. Bitman, T. Liu, J. Liu, E. Paschalis, B. Patel, C. Nawrocki, K. Xu, L. Nieman, D. Ting, N. Thimmiah, S. Sun, R. Abelman, V. Bossuyt, S. Isakoff, L. Spring, A. Bardia, L. Ellisen
Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. To identify mechanisms regulating immune infiltration in TNBC, we performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold tumors. We reveal that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in TNBC through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and predicts poor outcomes in TNBC. Loss-of-function and reconstitution experiments demonstrate TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of the ADC Sacituzumab govitecan (SG), enhances the anti-PD1 response and improves T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Thus, TROP2 controls an immune exclusion program that can be targeted to enhance immunotherapy response. Citation Format: B. Wu, W. Thant, E. Bitman, T. Liu, J. Liu, E. Paschalis, B. Patel, C. Nawrocki, K. Xu, L. Nieman, D. Ting, N. Thimmiah, S. Sun, R. Abelman, V. Bossuyt, S. Isakoff, L. Spring, A. Bardia, L. Ellisen. Trop2 remodeling of the immune microenvironment in triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS3-12-29.
免疫排斥抑制抗肿瘤免疫和对免疫治疗的反应，但其机制仍不明确。三阴性乳腺癌（TNBC）是一种侵袭性且通常免疫丰富的亚型，由于对化疗和免疫检查点抑制剂的反应有限，免疫冷微环境预示着预后不良。为了确定TNBC中调节免疫浸润的机制，我们进行了空间转录组分析，比较了免疫富集和免疫冷肿瘤。我们发现，作为抗癌抗体药物偶联物（adc）的关键靶点，滋养细胞表面抗原2 （Trophoblast Cell-Surface Antigen 2, TROP2）通过Claudin 7关联和紧密连接调控TNBC中屏障介导的免疫排斥。TROP2表达与T细胞浸润呈负相关，并预测TNBC的不良预后。功能缺失和重建实验表明，TROP2足以在体内以CD8 T细胞依赖的方式驱动肿瘤进展，而它的缺失会调节多种紧密连接蛋白的表达和定位，使T细胞浸润。通过人源化TROP2同基因TNBC模型，我们发现TROP2通过ADC Sacituzumab govitecan （SG）的抗体成分hRS7靶向，增强了抗pd1反应，提高了T细胞的可及性和效应功能。相应地，在人类乳腺癌中，TROP2的表达与抗pd1治疗缺乏反应高度相关。因此，TROP2控制一个免疫排斥程序，可以靶向增强免疫治疗反应。引用格式：B. Wu， W. Thant， E. Bitman， T. Liu， J. Liu， E. Paschalis， B. Patel， C. Nawrocki， K. Xu， L. Nieman， D. Ting， N. Thimmiah， S. Sun， R. Abelman， V. Bossuyt， S. Isakoff， L. Spring， A. Bardia， L. Ellisen三阴性乳腺癌中免疫微环境的Trop2重塑[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS3-12-29。
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Pub Date : 2026-02-17DOI: 10.1158/1557-3265.sabcs25-ps5-02-20
A. Konieczna, M. Holanek, M. Pieniazek, J. Zubrowska, A. Polakiewicz-Gilowska, R. Soumarova, H. Studentova, A. Mlodzinska, K. Winsko-Szczesnowicz, M. Lisik-Habib, A. Pekala, D. Krejci, J. Sustr, I. Kolarova, I. Kolouskova, I. Danielewicz, M. Szymanik-Resko, T. Ciszewski, L. Rusinova, B. Czartoryska-Arlukowicz, A. Lacko, M. Jarzab, R. Pacholczak-Madej, Z. Bielcikova, M. Malejcikova, M. Puskulluoglu
Background: Patients over 65 years constitute a substantial subset of those diagnosed with metastatic triple-negative breast cancer (mTNBC), yet are frequently underrepresented in clinical trials due to comorbidities, frailty, and polypharmacy. Sacituzumab govitecan (SG), approved for pretreated mTNBC, demonstrated comparable efficacy and tolerability in this age group in the ASCENT trial. However, real-world data remain limited. This multinational study investigates the safety and effectiveness of SG in patients aged >65 years treated in routine clinical practice. Materials and Methods: We retrospectively analyzed clinical data from female patients receiving SG across 18 oncology centers in Slovakia, Poland, and the Czech Republic between August 2021 and May 2025. Patients were stratified by age at SG initiation (≤65 vs. >65 years). Baseline characteristics, treatment patterns, and adverse events (graded according to CTCAE v5.0) were compared. Clinical information was extracted retrospectively from routine medical records. The analysis included progression-free survival (PFS; time from SG initiation to progression or death), overall survival (OS; time from SG initiation to death from any cause), objective response rate (ORR), and disease control rate (DCR) as clinical endpoints. Tumor responses were evaluated according to RECIST 1.1. Univariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. Results: Among 303 patients included, 76 (25.1%) were >65 years. Only 10 of them (13.2%) underwent geriatric assessment as part of routine clinical practice. Older patients had received a higher number of prior palliative systemic therapies (median 2 [IQR 1-2] vs. 1 [IQR 1-2], p=0.039). Visceral metastases (77.5% vs. 60.5%, p=0.006) and central nervous system (CNS) metastases (11.5% vs. 2.6%, p=0.038) were more frequent in the younger group. A reduced starting dose of SG (≤8 mg/kg at cycle 1 day 1) was used in 13.2% of older and 7.5% of younger patients (p=0.204). Adverse event-related dose reductions occurred in 46.1% of individuals >65 and 34.8% ≤65 (p=0.106). Delays in SG administration were observed in 71.1% and 60.4%, respectively (p=0.125). Grade ≥3 neutropenia occurred in 42.1% vs. 45.8% (p=0.733). No other significant differences in toxicity were detected. Median number of full SG cycles was similar across age groups (7 [IQR 3-12] vs. 6 [IQR 3-10], p=0.240). ORR was 30.3% vs. 30.8% (p>0.999), and DCR was 72.4% vs. 61.7% (p=0.122). Survival analyses demonstrated that patients >65 years achieved significantly longer PFS and OS compared to younger individuals (median PFS: 5.42 vs. 4.07 months; HR=0.716; 95% CI: 0.534-0.960; p=0.026; and median OS: 12.81 vs. 10.91 months; HR=0.691; 95% CI: 0.485-0.985; p=0.041, respectively). Conclusions: Older women with mTNBC treated with SG in routine clinical practice
背景：65岁以上的患者构成了转移性三阴性乳腺癌（mTNBC）患者的一个重要组成部分，但由于合并症、虚弱和多种药物治疗，在临床试验中往往代表性不足。在ASCENT试验中，被批准用于预处理mTNBC的Sacituzumab govitecan （SG）在该年龄组中显示出相当的疗效和耐受性。然而，真实世界的数据仍然有限。这项跨国研究探讨了SG在老年患者中的安全性和有效性。65年临床常规治疗。材料和方法：我们回顾性分析了斯洛伐克、波兰和捷克共和国18个肿瘤中心在2021年8月至2025年5月期间接受SG治疗的女性患者的临床数据。患者按SG开始时的年龄分层（≤65岁vs.≤65岁）。比较基线特征、治疗模式和不良事件（根据CTCAE v5.0分级）。回顾性地从常规病历中提取临床资料。分析包括无进展生存期（PFS；从SG开始到进展或死亡的时间）、总生存期（OS；从SG开始到任何原因死亡的时间）、客观缓解率（ORR）和疾病控制率（DCR）作为临床终点。根据RECIST 1.1评估肿瘤反应。采用单因素Cox回归模型估计风险比（hr）和95%置信区间（ci）。P, lt;0.05认为有统计学意义。结果：纳入的303例患者中，76例（25.1%）为&；gt；65年。其中只有10人（13.2%）将老年评估作为常规临床实践的一部分。老年患者既往接受过更多的姑息性全身治疗（中位数为2 [IQR 1-2]比1 [IQR 1-2]， p=0.039）。内脏转移（77.5% vs. 60.5%, p=0.006）和中枢神经系统（CNS）转移（11.5% vs. 2.6%, p=0.038）在年轻组中更为常见。13.2%的老年患者和7.5%的年轻患者使用降低起始剂量的SG（第1周期第1天≤8 mg/kg） （p=0.204）。46.1%的个体出现了不良事件相关的剂量减少&；gt；≤65者占34.8% （p=0.106）。SG给药延迟分别为71.1%和60.4% （p=0.125）。≥3级中性粒细胞减少发生率为42.1%比45.8% （p=0.733）。在毒性方面未发现其他显著差异。各年龄组SG完整周期的中位数相似（7例[IQR 3-12]对6例[IQR 3-10]， p=0.240）。ORR为30.3%比30.8% (p>0.999)， DCR为72.4%比61.7% （p=0.122）。生存分析表明，患者&；gt；65岁患者的PFS和OS较年轻患者明显更长（中位PFS: 5.42 vs 4.07个月；HR=0.716; 95% CI: 0.534-0.960; p=0.026；中位OS: 12.81 vs 10.91个月；HR=0.691; 95% CI: 0.485-0.985; p=0.041）。结论：在常规临床实践中，接受SG治疗的mTNBC老年女性患者的PFS和OS明显长于年轻患者，尽管治疗暴露、毒性和反应率相似。这些发现挑战了年龄本身预测较差结果的假设，并支持在选定的老年人中使用SG。然而，只有13.2%的患者65岁的人接受了正式的老年评估，这表明可能存在对临床适合个体的选择偏差。观察到的生存优势也可能反映了较低的中枢神经系统和内脏转移率或较低的侵袭性肿瘤生物学。我们的研究结果强调了基于临床适应度而非年龄的个性化治疗决策的必要性，并支持将老年评估更广泛地整合到常规肿瘤学实践中。有必要进行前瞻性研究，以阐明与年龄相关的结果差异的生物学和临床驱动因素。引用格式：A. Konieczna， M. Holanek， M. Pieniazek， J. Zubrowska， A. Polakiewicz-Gilowska， R. Soumarova， H. Studentova， A. Mlodzinska， K. Winsko-Szczesnowicz， M. Lisik-Habib， A. Pekala， D. Krejci， J. Sustr， I. Kolarova， I. Kolouskova， I. Danielewicz， M. Szymanik-Resko， T. Ciszewski， L. Rusinova， B. Czartoryska-Arlukowicz， A. Lacko， M. Jarzab， R. Pacholczak-Madej， Z. Bielcikova， M. Malejcikova， M. Puskulluoglu。sacituzumab govitecan在老年与年轻mTNBC患者中的治疗模式和结果：多国真实世界数据[摘要]。摘自：《2025年圣安东尼奥乳腺癌研讨会论文集》；2025年12月9-12日；费城（PA）： AACR；临床癌症杂志2026；32（4增刊）：nr PS5-02-20。
{"title":"Abstract PS5-02-20: Treatment patterns and outcomes of sacituzumab govitecan in older versus younger patients with mTNBC: multinational real-world data","authors":"A. Konieczna, M. Holanek, M. Pieniazek, J. Zubrowska, A. Polakiewicz-Gilowska, R. Soumarova, H. Studentova, A. Mlodzinska, K. Winsko-Szczesnowicz, M. Lisik-Habib, A. Pekala, D. Krejci, J. Sustr, I. Kolarova, I. Kolouskova, I. Danielewicz, M. Szymanik-Resko, T. Ciszewski, L. Rusinova, B. Czartoryska-Arlukowicz, A. Lacko, M. Jarzab, R. Pacholczak-Madej, Z. Bielcikova, M. Malejcikova, M. Puskulluoglu","doi":"10.1158/1557-3265.sabcs25-ps5-02-20","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-02-20","url":null,"abstract":"Background: Patients over 65 years constitute a substantial subset of those diagnosed with metastatic triple-negative breast cancer (mTNBC), yet are frequently underrepresented in clinical trials due to comorbidities, frailty, and polypharmacy. Sacituzumab govitecan (SG), approved for pretreated mTNBC, demonstrated comparable efficacy and tolerability in this age group in the ASCENT trial. However, real-world data remain limited. This multinational study investigates the safety and effectiveness of SG in patients aged &gt;65 years treated in routine clinical practice. Materials and Methods: We retrospectively analyzed clinical data from female patients receiving SG across 18 oncology centers in Slovakia, Poland, and the Czech Republic between August 2021 and May 2025. Patients were stratified by age at SG initiation (≤65 vs. &gt;65 years). Baseline characteristics, treatment patterns, and adverse events (graded according to CTCAE v5.0) were compared. Clinical information was extracted retrospectively from routine medical records. The analysis included progression-free survival (PFS; time from SG initiation to progression or death), overall survival (OS; time from SG initiation to death from any cause), objective response rate (ORR), and disease control rate (DCR) as clinical endpoints. Tumor responses were evaluated according to RECIST 1.1. Univariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). P &lt; 0.05 was considered statistically significant. Results: Among 303 patients included, 76 (25.1%) were &gt;65 years. Only 10 of them (13.2%) underwent geriatric assessment as part of routine clinical practice. Older patients had received a higher number of prior palliative systemic therapies (median 2 [IQR 1-2] vs. 1 [IQR 1-2], p=0.039). Visceral metastases (77.5% vs. 60.5%, p=0.006) and central nervous system (CNS) metastases (11.5% vs. 2.6%, p=0.038) were more frequent in the younger group. A reduced starting dose of SG (≤8 mg/kg at cycle 1 day 1) was used in 13.2% of older and 7.5% of younger patients (p=0.204). Adverse event-related dose reductions occurred in 46.1% of individuals &gt;65 and 34.8% ≤65 (p=0.106). Delays in SG administration were observed in 71.1% and 60.4%, respectively (p=0.125). Grade ≥3 neutropenia occurred in 42.1% vs. 45.8% (p=0.733). No other significant differences in toxicity were detected. Median number of full SG cycles was similar across age groups (7 [IQR 3-12] vs. 6 [IQR 3-10], p=0.240). ORR was 30.3% vs. 30.8% (p&gt;0.999), and DCR was 72.4% vs. 61.7% (p=0.122). Survival analyses demonstrated that patients &gt;65 years achieved significantly longer PFS and OS compared to younger individuals (median PFS: 5.42 vs. 4.07 months; HR=0.716; 95% CI: 0.534-0.960; p=0.026; and median OS: 12.81 vs. 10.91 months; HR=0.691; 95% CI: 0.485-0.985; p=0.041, respectively). Conclusions: Older women with mTNBC treated with SG in routine clinical practice","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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