Bakhtiar Hamza, Sharifi Marina N, Helzer Kyle T, Shi Yue, Bootsma Matthew L, Shang Tianfu A, Chrostek Matthew R, Berg Tracy J, Carson Callahan S, Carreno Viridiana, Blitzer Grace C, West Malinda T, O'Regan Ruth M, Wisinski Kari B, Sjöström Martin, Zhao Shuang G
Department of Human Oncology, University of Wisconsin, Madison, WI, USA.
Department of Medicine, Division of Hematology, Oncology, and Palliative Care, University of Wisconsin, Madison, WI, USA.
NPJ Precis Oncol. 2024 Oct 2;8(1):220. doi: 10.1038/s41698-024-00722-7.
In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.
在临床前研究中，p53功能丧失会影响化疗反应，但这在临床上尚未得到一致验证。我们从TCGA的泛癌临床样本中训练了一种TP53缺失表型模拟基因表达特征。在体外，TP53缺失表型模拟特征可预测不同癌症类型的化疗反应。在一个包含3003例接受新辅助化疗的乳腺癌样本的临床数据集中，TP53缺失表型模拟样本出现病理完全缓解（pCR）的可能性要高56%，在雌激素受体（ER）阳性和ER阴性肿瘤中，TP53缺失表型模拟与pCR之间均存在显著关联。在I-SPY2试验（N = 987）的独立临床验证中，我们证实了其与新辅助化疗pCR的关联，并发现与非TP53缺失表型模拟肿瘤相比，TP53缺失表型模拟肿瘤的化学免疫治疗反应率更高（64%对28%）。TP53缺失表型模拟特征在体外可预测不同癌症类型的化疗反应，并且在一项概念验证临床验证中，与多个临床乳腺癌队列的新辅助化疗反应相关。
