Page 34 - Read Online

Briggs et al. J Cancer Metastasis Treat 2021;7:46 https://dx.doi.org/10.20517/2394-4722.2021.84 Page 3 of 13

PROGNOSTIC BIOMARKERS
Serum biomarkers, such as ALP, corrected calcium, Hg, LDH, neutrophil count, and platelets have been
[12]
[10]
[11]
extensively validated as prognostic biomarkers for OS and CSS by MSKCC , CCF , IMDC , Groupe
Français d'Immunothérapie , International Kidney Cancer Working Group and others [Table 1,
[14]
[15]
Supplementary Table 1]. Additional promising serum biomarkers include elevated carbonic anhydrase IX
(CAIX) being potentially prognostic of improved PFS and OS , while elevated COP-NLR , elevated
[16]
[17]
[18]
[19]
CRP , s-TATI , and VEGF [15,16,20] may be prognostic for decreased PFS and/or OS . Conflicting or
[19]
[21]
[16]
inconclusive evidence exists regarding Ras p21 , sVEGF-r , TIMP-1 mRNA [16,22] . For example, elevated
TIMP-1 mRNA has been positively associated with metastasis and OS in one study but negatively
[22]
[16]
associated with OS in another .
Among certain patient populations, mutated alleles that may be prognostic for poorer OS or PFS compared
[24]
[23]
to wild type (WT) include loss of function (LOF) mutations or alterations in BAP1 , CDKN2A , CIMP
/FH , and TERT [Table 2, Supplementary Table 2]. Limited evidence has linked tumor mutational
[24]
[23]
burden (TMB) with poor OS and PFS; however, most has shown no significant association [25-30] . The
prognostic value of PBRM-1 LOF mutations has proven inconsistent, with some studies reporting longer OS
or PFS in patients receiving nivolumab [31,32] , but no significant difference in patients receiving everolimus,
sunitinib, or combination therapy [27,28,32,33] . Limited evidence also suggests that OS may be longer in patients
with PBRM-1 LOF mutations and pancreatic metastasis than without . Additionally, PBRM-1 LOF
[33]
mutations have been associated with less immunogenic, more angiogenic tumor microenvironments, which
may portend a worse prognosis . The prognostic value of PBRM-1 mutations as a marker of survival may
[33]
depend on the specific treatment used. Conflicting or inconclusive evidence exists regarding whether
[28]
mutated alleles in ERV , mTOR , and VHL are prognostic for OS or PFS. Finally, SETD2 may be
[25]
[28]
associated with metastatic spread to bone .
[34]
Expression of single genes and gene expression signatures (GES) may also be prognostic for OS and PFS
[Table 2, Supplementary Table 2]. Increased expression of ERV has been shown to be prognostic for
improved PFS [35,36] , while expression of NQO1 has been associated with shorter OS . Expression of DUX4
[24]
GES has not been shown to be prognostic . The prognostic value of GES IMmotion 150 Angio, IMmotion
[28]
150 Myeloid, IMmotion 150 Teff, Renal 101 Immuno, and Renal 101 Angio will be discussed separately,
along with their predictive value [28,29] .
Finally, histologic biomarkers have shown prognostic value [Table 2, Supplementary Table 2]. High levels of
CAIX have a demonstrated association with improved DFS (HR = 0.69, P = 0.01), OS (HR = 0.60, P = 0.01),
and CSS (HR = 0.69, P = 0.01) ; similarly, in a separate study, low levels of CAIX were linked to decreased
[21]
CSS (HR = 3.10, P < 0.001) . Additionally, given the complex interplay between T-cells and RCC cancer
[37]
cells, the infiltration of various areas of tumors by CD8+ T-cells has been examined. While higher CD8+ T-
cell density in tumor centers and invasive margins has been associated with improved PFS in patients
receiving sunitinib, no significant difference was noted amongst patients receiving avelumab plus
[28]
axitinib . On the other hand, macrophage infiltration has been associated with poorer OS and PFS in
patients receiving anti-angiogenic TKI, though the limited study has examined macrophage infiltration and
outcomes with other therapies .
[38]
Overall, we found the strongest consensus for serum levels of CAIX , COP-NLR , CRP , s-TATI , and
[16]
[18]
[17]
[19]
VEGF [15,16,20] , gene mutations in BAP1 , CDKN2A , CIMP/FH , and TERT , gene expression of
[23]
[24]
[23]
[24]
ERV [35,36] , and NQO1 , and histologic expression of CAIX [21,37] and macrophage infiltration as prognostic
[38]
[24]
biomarkers for OS and PFS. Tables 1 and 2, Supplementary Tables 1 and 2 list all identified data depicting