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Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76 Page 9 of 15

scenario, EASL guidelines recommend testing the combination of 3 immunohistochemical markers (GPC3,
HSP70 and GS). Besides, a 3-gene signature including GPC3, lymphatic vessel endothelial hyaluronan receptor 1,
and survivin has also been proposed as an accurate molecular tool (sensitivity of 95% and specificity of 94%) to
[108]
discriminate dysplastic nodules and HCCs smaller than 2 cm in the setting of HCV etiology . A step forward
in the diagnosis of HCC could be provided by the development of a “liquid biopsy”, i.e., the identification in
[109]
the peripheral circulation of CTCs or circulating tumor DNA that have detached from a primary tumor . A
[110]
recent paper reported preliminary data in 8 tumor types, including HCC .
Prognostic biomarkers for HCC
Regarding prognostic signatures for HCC, the phenotypic and molecular diversity of HCC allows us to identify
several new biomarkers.

Changes in AFP levels have been used for prognostic stratification at a cut-off of > 500 ng/dL as a predictor of
[31]
drop-out in the list of transplantation and as a predictor of the outcome of patients in phase III trials testing
systemic therapies such as transarterial therapies or Sorafenib.

Furthermore, an excellent prognostic ability has also been reported for some genetic signatures obtained from
tumor specimens in HCC patients treated by liver resection. Indeed, a 5-gene score based on the expression of
TAF9, RAN, RAMP3, KRT19 and HN1 genes, represents the most reliable predictor of survival identified so far
[111]
in multiple cohorts . Also, neoangiogenesis-related genes (a panel of microRNA associated with regulation of
angiogenesis) seem to be hallmarks of fast-growing HCCs and worst survival . Finally, a 186-gene score from
[112]
adjacent to tumor tissue was shown to have independent prognostic significance to predict overall survival in
[113]
HCC patients .

The use of biomarkers as predictors of response to therapeutic targets to HCC
The possibility of using novel biomarkers to predict tumor behavior to targeted therapies is appealing. Such
biomarkers are the FGF that are essential pathway components of oncogenesis. FGF3/FGF4 amplification was
[114]
found to predict increased response to the sorafenib in patients with HCC . Sorafenib is a targeted therapy,
classified as a tyrosine kinase inhibitor, has been the standard of care for patients with advanced HCC for
[115]
the last decade . Other predictive markers for sorafenib efficacy include high levels of soluble stem-cell
factor receptor c-Kit and low levels of hepatocyte growth factor which have shown a non-significant trend for
sorafenib efficacy [116,117] . Furthermore, patients with HCV-related HCC showed a higher benefit from sorafenib
[118]
(HR: 0.47) compared to non-HCV patients (HR: 0.81) .
Other targeted therapies for HCC include lenvaitinb [119] and regorafenib [118] as first-line treatments and
[121]
cabozantinib [120] and ramucirumab as second-line treatments. In phase III REACH-2 trial, Zhu et al. [121]
demonstrated that ramucirumab as a second-line treatment achieved a significant and meaningful overall
survival benefit with a favorable safety profile in HCC patients with baseline AFP greater than or equal
to 400 ng/mL, a population associated with poor prognosis; ramucirumab decreased mortality by 29% vs.
placebo as a second-line treatment for patients with advanced HCC and that AFP is a predictor of the efficacy
of ramucirumab. Although AFP could predict the efficacy of ramucirumab, there is still a need for more
[121]
biomarkers that show survival benefits for other HCC treatments .
Another targeted drug for HCC, nivolumab, in a recent phase I-II clinical trial of 260 patients with advanced
HCC has shown up to 16% of objective responses, some of them of long duration, obtaining a median overall
[122]
survival of 16 months . Again, the biomarkers used, the programmed death-1 and its ligand immunostain-
[123]
ing status did not predict response to nivolumab .
Recently, a gene signature capturing the immune class of HCC (~30% of patients) is currently under
investigation as a treatment response predictor .
[124]