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Page 12 of 25 Battaglin et al. J Cancer Metastasis Treat 2018;4:12 I http://dx.doi.org/10.20517/2394-4722.2018.04

[154]
in non-responders and low in patients who benefitted from bevacizumab (P = 0.0001) . All these potential
biomarkers, however, still need validation.

As novel anti-angiogenic agents have entered clinical practice in recent years, the interest was directed to
identify specific biomarkers for each compound. A retrospective analysis of ctDNA from liquid biopsies
collected from about 350 patients treated with regorafenib in the CORRECT trial was performed to investigate
the impact of KRAS, PIK3CA and BRAF mutations on regorafenib efficacy. Results were consistent with
previous data and confirmed that the benefit from regorafenib on survival and treatment outcomes was
[155]
irrespective of KRAS and PIK3CA mutational status . The analysis according to BRAF mutational status,
on the other hand, was not feasible due to the small number of BRAF-mutated patients. Data on RAS, BRAF
and sidedness as biomarkers in patients treated with aflibercept in the VELOUR trial have been recently
presented as well. No significant interactions according to RAS and BRAF status were found in this analysis,
although a trend for better outcomes was observed for BRAF-mutated tumors treated with aflibercept in
comparison with the control arm (mOS 10.3 vs. 5.5 months, respectively, HR 0.42; 95% CI, 0.16-1.09; P =
0.08) . Similar results were observed in patients treated with ramucirumab within the RAISE trial. In
[156]
fact, the ramucirumab favorable treatment effect was similar between RAS-mutated and all RAS/RAF WT
tumors; however, the benefit was more notable in BRAF-mutated tumors both for OS (HR 0.54; 95% CI
0.25-1.13) and PFS (HR 0.55; 95% CI 0.28-1.08) . Additionally, Tabernero et al. assessed the correlations
[158]
[157]
of a series of baseline marker levels (including VEGFR-2 immunohistochemistry in tumor tissue) with
clinical outcomes in the RAISE patients population. Only VEGF-D circulating serum levels were found to
be statistically significant with higher levels of this soluble factor (≥ 115 pg/mL) associated with improved
ramucirumab efficacy in comparison with placebo .
[158]
Several SNPs in different genes involved in VEGF signaling pathway have been investigated over time. Results
from a large meta-analysis including 158 SNPs and 1348 patients enrolled in five phase III randomized trials
suggested an association between VEGFA rs699946 and VEGFR-2 rs11133360 polymorphisms and improved
PFS in bevacizumab-treated patients . Unfortunately, additional promising retrospective findings on
[159]
different candidate SNPs of VEGF/VEGFR pathway genes were not prospectively validated in a dedicated
[160]
study .

DNA methylation
Over the last decade, evidence on the role of the epigenome in CRC has been largely explored and it is
now recognized that among thousands of epigenetic alterations which can be present in each tumor, a
small subgroup may be considered a driver event in CRC development . Different epigenetic mechanisms,
[161]
in fact, can play a key role in carcinogenesis, such as DNA methylation, nucleosome positioning, histone
modifications and non-coding RNAs expression . Technological advances have considerably increased
[162]
our ability to detect a wide number of epigenetic alterations which can eventually have a role as clinical
biomarkers for early detection, prognostic stratification and treatment efficacy prediction in CRC patients.
Of note, recently the availability of more refined genome-wide mapping technologies, highlighted that
the function of DNA methylation can vary depending on its context, underlining a deep complexity that
[163]
warrants further evaluations .
Aberrant DNA methylation is the most extensively studied epigenetic mechanism in CRC. Global DNA
hypomethylation is currently considered a common feature of CRC; on the other hand, however, evidence
on the role of CpG islands DNA hypermethylation in promoting CRC by silencing the expression of tumor
suppressor genes led to the identification of the CpG Island Methylator Phenotype (CIMP), consisting
in a subset of CRCs characterized by distinct epidemiological, histological and molecular features and
prognosis . CIMP+ tumors are associated with female gender and older age, show more frequently a right-
[164]
sided colon location, a high incidence of BRAF V600E mutation and MSI-H status as a consequence of MLH1