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Page 6 of 13 Briggs et al. J Cancer Metastasis Treat 2021;7:46 https://dx.doi.org/10.20517/2394-4722.2021.84

More relevant to the era of checkpoint inhibitors, TERT promoter mutations may be predictive of resistance
to ICI, as one study found TERT promoter mutations to be enriched in patients experiencing no clinical
[43]
benefit in the ICI cohort . High expression of hERV has been associated with improved response to ICI
and nivolumab [35,36] . High expression of a 5-Gene panel (FOXP3, CCR4, KLRK1, ITK, and TIGIT) has been
associated with improved response to ICI . PBRM-1 LOF mutations have been associated with longer OS
[44]
and PFS and increased ORR in patients receiving nivolumab monotherapy [25,31-33] , but no significant
difference in OS or PFS in patients receiving everolimus, sunitinib, or combination therapy [27,28,32,33] .
However, these findings are not universally consistent as PBRM-1 mutations have also been associated with
decreased ORR in patients receiving atezolumab monotherapy and improved TTF in patients receiving
[33]
[23]
anti-VEGF therapy . TMB has not been associated with differential ORR to ICI, nivolumab, or
everolimus [25,26,45,46] .

Overall, CRP and mutations in MET, PBRM-1, and BAP1 be associated with improved response to
TKIs [18,23,39] , while mutations in the mTOR pathway and expression of PTEN may be associated with
improved response to mTOR inhibitors [40-42] . TERT promoter mutations, hERV expression, and T-effector
expression may be associated with improved response to ICI [35,36,43,44] . Table 3 and Supplementary Table 3 list
all identified data depicting the value of these biomarkers in predicting response to various treatments.

SELECT GENE EXPRESSION SIGNATURES AS PROGNOSTIC AND PREDICTIVE
BIOMARKERS
Aberrantly upregulated VEGF pathways cause angiogenesis necessary for continued tumor growth, while
PDL1 expression by tumor and tumor-infiltrating cells suppresses the immune response to the tumor. As
these two aspects of the mRCC disease state have been increasingly well-defined, a number of GES reflective
of angiogenic and immunogenic pathways have been evaluated for their prognostic and predictive
[29]
implications across multiple large databases of patients with mRCC. In 2019, McDermott et al. defined
three such GES in an analysis of the IMmotion 150 cohort that included genetic expression related to
angiogenesis (coined, “IMmotion 150 Angio”, including expression of VEGFA, KDR, ESM1, PECAM1,
ANGPTL4, CD34), myeloid inflammation (coined “IMmotion 150 Myeloid”, including IL-6, CXCL1,
CXCL2, CXCL3, CXCL8, and PTGS2), and immune activation including effector T-cell (Teff) presence and
function, IFN-γ response, checkpoint inhibitors, and antigen presentation (coined “IMmotion 150 Teff”,
including CD8A, EOMES, PRF1, IFNG, and CD274). Similarly, in 2020, Motzer et al. defined two GES in
[28]
an analysis of the JAVELIN Renal 101 cohort that analyzed the expression of 26 genes each, coined “Renal
101 Immuno” (most similar to IMmotion 150 Teff) and “Renal 101 Angio”. The extent to which high
expression vs. low expression (as defined by gene expression ≥ or < median) of these five GES is associated
with OS, PFS, or ORR has been examined across the IMmotion 150 and 151 cohorts, the JAVELIN phase 1
and RENAL 100 and 101 cohorts, and the CheckMate 214 cohort as depicted in Table 4 and Supplementary
Table 4.

Examining cancer angiogenesis, high vs. low expression of both the IMmotion 150 Angio and the JAVELIN
Renal 101 Angio GES have been associated with improved PFS and ORR in patients receiving
sunitinib [27,29,47] . However, in patients receiving combination nivolumab + ipilimumab therapy, those with
high expression of IMmotion 150 Angio demonstrated decreased ORR , and in patients with low
[27]
IMmotion 150 Angio receiving combination atezolumab + bevacizumab vs. sunitinib, decreased PFS has
been shown . Furthermore, high IMmotion 150 Angio GES has been associated with favorable (vs.
[29]
[48]
intermediate/poor) risk . Finally, Beuselinck et al. established an angiogenic GES that has been
[47]
[38]
associated with improved ORR to anti-angiogenic therapy across three cohorts . Thus, while these
angiogenic GES may predict improved response to targeted anti-angiogenic therapy compared with ICI or