Page 10 - Read Online

Atmaja et al. J Cancer Metastasis Treat 2021;7:xx https://dx.doi.org/10.20517/2394-4722.2021.66 Page 5 of 14

[36]
type 2 and a poorer prognosis .

Investigating the efficacy of MET-directed therapies in pRCC is an area of ongoing research. A phase II trial
demonstrated that the presence of a MET mutation in pRCC is highly predictive of a response to the MET
[38]
[37]
inhibitor, Foretinib . Furthermore, Choueiri et al. concluded an improved objective response rate (ORR)
and progression-free survival (PFS) with MET-driven disease on Savolitinib, another MET inhibitor.
Cabozantinib, a TKI, is already approved as a first or second-line therapy in ccRCC [39,40] ; the SWOG 1500
trial is currently evaluating its specific use in pRCC due to the prevalence of MET mutations in this subtype.
The results may alter the nccRCC treatment algorithm and the presence of a MET mutation could well be
used as a predictive biomarker for nccRCC in the future.

Other less common nccRCC are chromophobe (~5% of cases), oncocytoma (~3%-7% cases) and collecting
duct RCC (< 1% of cases), whereas sarcomatoid RCC is no longer considered as a true subtype as
sarcomatoid differentiation is associated with all RCC types. Unlike ccRCC and pRCC, these rarer subtypes
are thought to arise from the distal nephron, likely the epithelium of collecting tubules. Unlike in ccRCC,
VHL mutation has not been found in the chromophobe subtype. However, point mutation of p53 is
significantly more common (~25%) as well as upregulation of KIT proto-oncogene, although gene
sequencing did not show any activating point mutation [41-44] . Collecting duct RCC meanwhile shows loss of
heterozygosity of chromosome 1q, 6p, 13q and 21q .
[45]
Circulating tumor markers
Circulating tumor DNA (ctDNA) may accelerate biomarker discovery and provide the future solution for a
more individualized approach to the management of mRCC.

Analysis has revealed extensive heterogeneity within primary RCC tumors; as such, several genetic
mutations may be overlooked by obtaining only a solitary tumor biopsy. Utilizing ctDNA for testing instead
provides us with a non-invasive method that could increase the likelihood of detecting genetic
alterations [46,47] .

A large study by Pal et al. , which evaluated the use of ctDNA in mRCC, found that genomic alterations
[48]
were identified peripherally in approximately 79% of patients; this included mutations of TP53, VHL,
EGFR, NF1 and ARIDIA. They also noted ctDNA variability during different lines of therapy; there was a
substantial increase in mutation frequency observed in patients on subsequent therapy, compared to first-
line . This data may help broaden our understanding of therapeutic resistance.
[47]

ACTIVE SURVEILLANCE IN METASTATIC RENAL CELL CARCINOMA
The traditional approach of initiating systemic therapy immediately after diagnosing metastatic disease has
been challenged in recent years. mRCC is a diverse disease with many different prognostic factors; patients
with low-risk or slowly progressive malignancy may instead benefit from an initial period of active
surveillance before starting systemic therapy . Several trials and analyses have demonstrated that this
[49]
approach may be advantageous in certain circumstances.

In 2014, Park et al. concluded that, in asymptomatic or minimally symptomatic patients, the response
[49]
rates and overall survival with deferred systemic treatment were comparable to those without a surveillance
period. Given the toxic and non-curative nature of therapy, this regime could positively impact a patient’s
quality of life.