Retrospective immunophenotypical evaluation of MET, PD-1/PD-L1, and mTOR pathways in primary tumors and pulmonary metastases of renal cell carcinoma: the RIVELATOR study addresses the issue of biomarkers heterogeneity

Author:

Bersanelli Melissa1ORCID,Gnetti Letizia2ORCID,Pilato Francesco Paolo2,Varotti Elena3,Quaini Federico4,Campanini Nicoletta5,Rapacchi Elena1,Camisa Roberta1,Carbognani Paolo6,Silini Enrico Maria5ORCID,Rusca Michele4,Leonardi Francesco1,Maestroni Umberto7,Rizzo Mimma8ORCID,Brunelli Matteo9ORCID,Buti Sebastiano10,Ampollini Luca11

Affiliation:

1. Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy

2. Pathologic Anatomy Unit, University Hospital of Parma, 43126 Parma, Italy

3. Pathologic Anatomy Unit, Azienda Socio-Sanitaria Territoriale di Cremona, 26100 Cremona, Italy

4. Medicine and Surgery Department, University of Parma, 43126 Parma, Italy

5. Pathologic Anatomy Unit, University Hospital of Parma, 43126 Parma, Italy; Medicine and Surgery Department, University of Parma, 43126 Parma, Italy

6. Medicine and Surgery Department, University of Parma, 43126 Parma, Italy; Medicine and Surgery Department, University of Parma, 43126 Parma, Italy

7. Urology Unit, University Hospital of Parma, 43126 Parma, Italy

8. Medical Oncology Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico, 70124 Bari, Italy

9. 8.Pathologic Anatomy Unit, University Hospital of Verona, 37126 Verona, Italy; Medicine and Surgery Department, University of Verona, 37126 Verona, Italy; Medicine and Surgery Department, University of Verona, 37126 Verona, Italy

10. Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; Medicine and Surgery Department, University of Parma, 43126 Parma, Italy

11. Medicine and Surgery Department, University of Parma, 43126 Parma, Italy; Thoracic Surgery Unit, University Hospital of Parma, 43126 Parma, Italy

Abstract

Aim: 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). Methods: 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. Results: 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 (P = 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), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: 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.

Publisher

Open Exploration Publishing

Subject

Cancer Research,Oncology

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3