EAU 2018: Molecular Heterogeneity Between Primary Tumors and Metastases in Renal Cell Cancer

Copenhagen, Denmark (UroToday.com) Dr. Kerstin Junker from Germany discussed the molecular heterogeneity between primary tumors and metastases. According to Dr. Junker there are three types of tumor heterogeneity, including (i) intertumor heterogeneity, (ii) intratumor heterogeneity, and (iii) heterogeneity between primary tumors and metastases. Understanding the heterogeneity of metastatic disease allows selection of therapy targets and prediction of therapy responses. 

A landmark New England Journal of Medicine paper from 2012 [1] discovered intratumor heterogeneity and branched evolution by multiregion sequencing of a primary renal tumor and metastatic site. Subsequently, a study published last year assessed paired samples (primary and metastatic site) among 60 patients with RCC and found several different classes of mutations, including missense, nonsense, promoter, and splicing mutations. These were most commonly in VHL, PBRM1, SETD2 and BAP1. Among these 60 patients, 22% of pairs had identical mutations. 

Recent interest has been directed toward BAP1 and PBRM1. In a study specifically assessing immunohistochemistry of BAP1 and PBRM1 among 41 paired samples, there was (i) concordance for BAP1 in 83% of cases compare to 63% for PBRM1, (ii) intratumor heterogeneity among primary tumors in 10% of cases for BAP1 and 24% of PBRM1, (iii) intratumor heterogeneity among metastases in 2% of cases for BAP1 and 7% of cases for PBRM1 [2]. Eckel-Passow et al. also specifically assessed BAP1 and PBRM1 among 111 patients with paired samples who underwent immunohistochemistry [3]. There were 12 patients that had intrametastatic heterogeneity assessed of which there was concordance in 100% of BAP1 specimens and 92% of PBRM1 samples. Thirty-two patients had intermetastatic heterogeneity assessed between 2-4 metastases, with BAP1 concordance in 97% of cases and 97% of PBRM1 cases. 

Additional targets for assessing molecular heterogeneity between primary tumors and metastatic sites includes the MET copy number (with potential clinical implications for cabozantinib) and differential expression of PD-L1. Dr. Junker concluded by noting that (i) molecular heterogeneity between primary tumors and metastatic lesions exists, but depends on targets and related biomarkers, (ii) this is important for targeted selection and development of predictive biomarkers, and (iii) intrametastatic heterogeneity was lower compared to primary tumors.

1. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883-892.
2. Miura Y, Inoshita N, Ikeda M, et al. Loss of BAP1 protein expression in the first metastatic site predicts prognosis in patients with clear cell renal cell carcinoma. Urol Oncol 2017;35(6):386-391.
3. Eckel-Passow E, Serie DJ, Cheville JC, et al. BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: Tumor heterogeneity and concordance with paired primary tumor. BMC Urol 2017;17(1):19.

Presented by: Kerstin Junker, Saarland University, Homburg, Germany

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, twitter: @zklaassen_md at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark