Bersanelli Melissa, Gnetti Letizia, Pilato Francesco Paolo, Varotti Elena, Quaini Federico, Campanini Nicoletta, Rapacchi Elena, Camisa Roberta, Carbognani Paolo, Silini Enrico Maria, Rusca Michele, Leonardi Francesco, Maestroni Umberto, Rizzo Mimma, Brunelli Matteo, Buti Sebastiano, Ampollini Luca
Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy.
Pathologic Anatomy Unit, University Hospital of Parma, 43126 Parma, Italy.
Explor Target Antitumor Ther. 2023;4(4):743-756. doi: 10.37349/etat.2023.00165. Epub 2023 Aug 31.
In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC).
The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context.
High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity ( = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), = 0.019; MET expression was related to PD-1 expression on TILs ( = 0.041, = 0.41) and peritumoral lymphocytes (RILs; = 0.013, = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors.
In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.
在肾细胞癌（RCC）中，肿瘤异质性给生物标志物的开发和治疗管理带来了挑战，常常导致原发性和获得性耐药。本研究旨在评估转移性肾细胞癌（mRCC）中已知可成药靶点的肿瘤间、肿瘤内和病灶内异质性。
RIVELATOR研究是一项对25例原发性RCC及其配对肺转移灶的生物样本进行的单中心回顾性分析。分析的生物标志物包括MET、mTOR、PD-1/PD-L1通路和免疫背景。
显示出高度的多水平异质性。MET是最可靠的生物标志物，肿瘤内异质性最低：原发性肿瘤及其转移灶中MET表达之间的正相互相关性具有显著的比例强度（=0.038）。mTOR通路蛋白的肿瘤内异质性等级显著更高。发现了联合免疫表型表达模式及其与免疫背景的相关性[即转移灶中mTOR表达与肿瘤浸润淋巴细胞（TILs）中PD-L1表达呈正相关，=0.019；MET表达与TILs上的PD-1表达相关（=0.041，=0.41）以及瘤周淋巴细胞（RILs；=0.013，=0.49）]，提示预测对酪氨酸激酶、mTOR或免疫检查点抑制剂的药物反应或耐药性的可能性。
在mRCC中，需要对潜在的预测性生物标志物进行多次和多水平检测，以便将其可靠地转化为临床实践。本研究中易于使用的免疫组织化学方法能够识别不同的联合表达模式，为规划mRCC患者群体的全身治疗组合和顺序管理提供线索。所研究生物标志物的定量异质性表明，需要进行多次病灶内检测，以使评估对临床考虑而言可靠。
