ASCO 2018: Clinical Applications of the Biology of Renal Cancer
Below, I will try to highlight some of his key points. However, the depth of his talk precludes the ability to get into too much detail.
VHL gene mutations on chromosome 3p are important drivers for RCC development – Gerlinger et al (Nature Genetics 2014) demonstrated that >80% of RCC have VHL mutations, and indeed may occur 10-30 years prior to disease presentation (Mitchell et al. Cell 2018). However, recently, additionally genes on this chromosome have gained significant attention. Specifically, BAP1 and PBRM1 are both found on 3p, in close proximity to one another. Interestingly, while both are not uncommon (BAP1 ~12%, PBRM1 ~55%), mutations in both are rare (<3%) – they appear to be mutually exclusive. BAP1 mutations appear to lead to a more aggressive phenotype while PBRM1 mutations appear to lead to a more low-grade phenotype.
Joseph et al. (J Urol) demonstrated that PBRM1-/BAP1- patients do significantly worse than patients with one mutation and patients with PBRM+/BAP1+ do the best in terms of RCC-specific survival.
Another gene on 3p is SETD2 – and its mutations seems to modify PBRM1 clinical outcomes. Patients with PBRM1- genotype who also have a SETD2 mutation do much worse – so it seems to modify this phenotype to a slightly more aggressive RCC.
Similarly, TSC1 mutations also seem to shift PBRM1- patients to a more aggressive phenotype.
Based on this, three pathways seem to emerge:
1. VHL alone
2. VHL and PBRM1 – low grade RCC with modification by SETD2 or TSC1 mutations
3. VHL and BAP1 – high grade RCC
He then briefly discussed his team’s efforts to target the HIF-2 pathway downstream of VHL.
In terms of translational work, he noted that there have been a few studies looking at mutations in mTORC1 and proximal regulators (TSC1) as predictors of extended response to mTOR inhibitors (rapalogues).
Lastly, he briefly touched on PBRM1 as a potential biomarker of response to I/O therapy. Miao et al (Science 2018) – LOF mutations in PBRM1 were associated with clinical benefit and was independently validated.
Again, his talk was very translational research heavy with less emphasis on current clinical impact. Clearly, there is a lot of great work going on in the field!
Presented by: James Brugarolas, MD
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA