Current NCCN guidelines do not mention neoadjuvant therapy, however, level 1 data from ASSURE, S-TRAC, PROTECT and ATLAS offer clinical trials, observation or adjuvant sunitinib (as a level IIB recommendation) for patients with high-risk clear cell histologies. However, we know that in patients with advanced or metastatic RCC, the decision about surgery vs systemic therapy vs clinical trials first is largely depending upon who and where the patient is seen, as experts can debate the validity and utility of this data.
Dr. Uzzo proposes that in order to better understand how these tumors should be treated, we need to better understand Halstedian (linear) and Fisher (non-linear) cancer biology. As Dr. Siddhartha Mukherjee suggested, cancer is a complex and evolving clonal ecosystem. Dr. Uzzo recommended that using heterogeneity as a hallmark, selective intrinsic pressures lead to clonal evolution. Along with a variable latency time, failure to recognize/repair/rescue and selective extrinsic pressures may cause evolutionary advantage and therefore “cancer-specific death”.
Dr. Uzzo then reviewed three TRACERx articles published in Cell, that evaluated the evolution of renal cancer cell biology. The first demonstrated the driver event as the loss of the 3p 30-40 years prior to diagnosis. Loss of 4 tumors suppressor genes are seen (VHL, PBRM1, BAP1, SETD2) with an initial clonal expansion of only a few hundred cells with long latency. The second study, demonstrated 7 evolutionarily conserved clonal subtypes, each associated with different prognoses. Finally, the last showed that metastases clonally are more homogenous with few driver mutations than matched primaries and attenuated progression was noted in cases of increased intra-tumoral heterogeneity in the primary. It is hypothesized that metastatic competence is acquired gradually and this is a result of increased chromosomal complexity and genomic instability. Comparing progression-free survival and time based upon genomic phenotype leads to graphs which closely mirror the tumor stage.
Finally, comparing genomic instability with intratumor clonal heterogeneity helps predict clinical progression. In summary, low ICH and high instability often have rapid progression, whereas low ICH and low instability often have a slow progression. In the future, hopefully, we can attack the less promiscuous further upstream targets of early sub-clonal events and improve the timing with systemic therapies, potentially with circulating tumor cells and other biomarkers.
Dr. Uzzo ended with discussing the notion of possibly preventing renal cell cancers in the future by eradicating low volume 3p loss clones – this would likely require treatment of 50-110 patients in 10-20 year old to prevent 1 future clear cell cancer!
Presented by: Robert G. Uzzo, MD, FACS, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Written by: David B. Cahn, DO, MBS, Fox Chase Cancer Center, Philadelphia, Pennsylvania, @dbcahn, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona