Genomic Evolution of Oligometastatic Clear Cell Renal Cell Carcinoma Presenting Two Decades Following Radical Nephrectomy

This was a very interesting and unusual case of a patient who developed a solitary locoregional metastatic recurrence more than twenty years after undergoing radical nephrectomy for clear cell renal cell carcinoma (ccRCC). The metastatic deposit found in an adjacent lymph node was confirmed as ccRCC on biopsy, and resected without complication.

Cytogenomic microarray analysis and targeted DNA sequencing confirmed the clonal nature of the metastasis by revealing chromosomal alterations and gene mutations that were conserved from the primary tumor. They also showed how the metastatic deposit had evolved over the decades, acquiring a limited number of additional genetic alterations including a new missense mutation in BAP1, amplification of the VHL variant allele, and loss of heterozygosity in the segment of chromosome 17 containing the TP53 gene, any of which could have led to accelerated growth after a long period of clinical latency.

While case reports are only single data points, they can be powerful demonstrations of the extremes of disease behavior, as well as opportunities to test whether our understanding of disease processes holds up in edge cases. In this report, we chose to highlight how the case reinforces the findings of the landmark 2018 TRACERx Renal studies, published as three distinct manuscripts, which investigated the genetic bases for RCC growth, evolution, and metastasis respectively.

The TRACERx Renal studies have been immensely impactful in our understanding of the genetic basis of RCC, and I strongly encourage all who treat this disease to read these papers at least once.

Here, I will highlight just a few of the key findings that are pertinent to our case:

In Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal, Mitchell et al. (2018) conducted whole genome sequencing on biopsy samples of ccRCC, examining the early evolutionary trajectories of tumor development.¹ The authors identified simultaneous chromosome 3p loss and 5p gain (via chromothripsis) as the most common genetic abnormality found in ccRCC. By measuring the proportion of point mutations that occurred before and after chromothripsis and extrapolating from a known mutation rate, they estimated that this key driver event typically occurred 30-50 years prior to the diagnosis of kidney cancer.

In Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal, Turajlic et al. (2018) sequenced multiple foci within ccRCC tumors to map the evolutionary trajectories of primary tumor growth, and identified seven distinct evolutionary subtypes where the genetic characteristics were predictive of disease phenotype.² On one end of the spectrum, tumors with high genomic instability and multiple clonal driver mutations demonstrated rapid growth and poor prognoses. In contrast, small renal masses (<4cm) more frequently consisted of tumors with single driver mutations (most commonly VHL) and low genomic instability.

In Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal, Turajlic et al (2018) examined how primary tumor subtypes correlated to patterns of metastatic spread and identified three broad categories of disease progression.³

In the “Punctated Evolution” scenario, aggressive cancer cells with high genomic instability and multiple driver mutations rapidly proliferate to dominate the primary tumor and metastasize early and widely to multiple sites. In the “Branched Evolution” scenario, driving mutations are acquired sequentially as the tumor grows, leading to the proliferation of different subclones within the primary tumor, of which only a subset develops metastatic potential. The pattern of spread is typically more limited to oligometastatic or solitary metastatic disease. Finally, in the “Linear Evolution” scenario, the presence of only a single driver mutation (often VHL) and low genomic instability leads to slow growth with the acquisition of a few additional mutations and rate metastatic spread. The authors analyzed three cases of late metastatic spread, all to the pancreas and occurring 8-17 years after treatment of the primary tumor, and found that the metastatic tumors typically had few additional driving mutations beyond what was carried over from the primaries.

For our patient, the decision to proceed with metastasectomy was based on her age, overall good health, and absence of any other sites of metastasis on imaging. A meta-analysis of surgical metastasectomy for RCC by Ouzaid et al (2019) showed that some patients do benefit from resection of metastatic disease, especially those with late recurrences and solitary metastases.⁴ However, these data were all retrospective, and the selection of the appropriate patients for metastasectomy remains a challenging decision with high stakes consequences on patient morbidity and mortality. As techniques for genetic analysis become cheaper and more accessible, we can envision a future where sequencing of the primary tumor helps inform these decisions: A patient with a solitary metastasis following nephrectomy who has a primary tumor containing multiple driver mutations and high genomic instability may be offered neoadjuvant therapy to treat presumed micrometastatic disease, while a similar patient with a higher intratumor heterogeneity and low genomic instability of their primary tumor may be a better candidate for upfront resection of their solitary metastasis. Fortunately for our patient, retrospective genetic testing has placed her within the latter category, and she remains disease-free one year after her metastasectomy.

Written by: Robert S. Wang, MD, and Robert G. Uzzo MD, MBA

Department of Urology, Fox Chase Cancer Center, Philadelphia, PA

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