Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine.
Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine.
复制标题
DOI：
10.1158/1078-0432.ccr-22-2191
复制
发表时间：
2023-01-17
期刊：
影响因子：
--
通讯作者：
Martin M
中科院分区：
文献类型：
--
作者：
Asleh K;Lluch A;Goytain A;Barrios C;Wang XQ;Torrecillas L;Gao D;Ruiz-Borrego M;Leung S;Bines J;Guerrero-Zotano Á;García-Sáenz JÁ;Cejalvo JM;Herranz J;Torres R;Haba-Rodriguez J;Ayala F;Gómez H;Rojo F;Nielsen TO;Martin M
卡培他滨在三阴性乳腺癌（TNBC）中获益的预测性生物标志物最近被提出使用III期临床试验的样本，包括非基础表型和与血管生成、基质和卡培他滨激活基因相关的生物标志物。我们的目标是在更大规模的GEICAM/CIBOMA III期临床试验中验证这些发现。随机分配到标准（新）辅助化疗后卡培他滨与观察组的TNBC患者的肿瘤组织使用测量mRNA表达的164个基因NanoString定制nCounter代码集进行分析。一项预先设定的统计计划旨在验证PAM50非基础分子亚型的预测能力，并验证了细胞毒性细胞、肥大细胞、内皮细胞、PDL2和38个个体基因（meta）基因表达增加的乳腺肿瘤在辅助卡培他滨的远端无复发生存期（DRFS；主要终点）和总生存期方面受益的假设。在参加GEICAM/CIBOMA试验的876名妇女中，658名（75%）可评估分析（337名使用卡培他滨，321名未使用卡培他滨）。在这些病例中，553例（84%）被诊断为PAM50基底样，105例（16%）被诊断为PAM50非基底样。非基础亚型是卡培他滨获益的最显著预测因子[hr卡培他滨，0.19；95%置信区间（CI）， 0.07-0.54；P <0.001]，与基础样PAM50 （HRcapecitabine, 0.9; 95% CI, 0.63-1.28; P = 0.55； P相互作用<0.001，调整后P值= 0.01）。对PAM50非基底亚型相关生物学过程的分析显示，其在肥大细胞、细胞外基质、血管生成以及间充质茎样TNBC亚型的特征中富集。在这项预先指定的GEICAM/CIBOMA试验的相关分析中，PAM50非基础状态确定了早期TNBC患者最有可能从卡培他滨获益。
Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial. Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival. Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07–0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63–1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype. In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine.