Introduction
Hepatocellular carcinoma (HCC) accounts for about 90% of liver cancers.
Most patients with HCC are diagnosed at an advanced tumor stage when
treatment options are very limited. Until 2018, when lenvatinib was
approved, sorafenib was considered the gold standard in the first-line
setting for the treatment of advanced HCC.1 However,
choosing between these two agents remains challenging due to their low
impact on survival and their similar and well-tolerated safety
profiles.2 Recently, the atezolizumab-bevacizumab
combination has emerged as the first-line systemic treatment, but
sorafenib is still a relevant choice for refractory patients and those
ineligible for immunotherapy.3 Sorafenib exerts its
action through the inhibition of tumor cell proliferation and
angiogenesis via the targeting of several oncogenic signaling pathways
involving serine/threonine and tyrosine kinases (RAF1, BRAF, VEGFR 1, 2,
3, PDGFR, KIT, FLT3, FGFR1, and RET).4,5 However,
sorafenib resistance remains a major challenge for improving the
effectiveness of HCC treatment. The underlying mechanisms for
inter-individual variability in response to therapy have not been fully
elucidated, and no validated markers have been found that are capable of
predicting clinical outcomes or sorafenib
tolerability.6,7 Thus, the identification of suitable
biomarkers for patient stratification for sorafenib response in HCC may
potentially help physicians in guiding the selection of tailored
treatments.
HCC is a hypervascular tumor in which angiogenesis plays an important
role for tumor growth and progression. Among others, VEGF/VEGFR,
angiopoietin (ANGPT), endothelial nitric oxide synthase (eNOS or NOS3),
and hypoxia-inducible factor-1α (HIF-1α) signaling play an important
role in regulating tumor angiogenesis.8 Single
nucleotide polymorphisms (SNPs) in angiogenesis-related genes have been
reported to influence outcomes in HCC patients treated with
sorafenib.9-11
In the present study, we selected 5 SNPs in these angiogenesis-related
genes for the genotyping of 34 HCC patients, of which 9 showed response
(responders) to therapy and 25 no response (non-responders).
Additionally, in a subgroup of HCC patients, we evaluated 1,931 SNPs and
5 copy number variations in 231 genes involved in drug absorption,
distribution, metabolism, and excretion (ADME) using the DMET Plus
microarray assay for the identification of new potential predictive
biomarkers of response and outcome.12-14 Through a
model learning process, we proceeded to apply rules to classify all
patients in terms of the detected SNPs and genotypes and according to
sorafenib response in order to identify a predictive genetic signature
which could allow the stratification of non-responder/responder patients
to sorafenib for tailored prescriptions. Furthermore, the correlation
between angiogenesis- and ADME-related genes was confirmed by a
cumulative genetic risk score (GRS) and by network and pathway
enrichment analysis, which demonstrated the association of 8/12
identified genes placed in topological key points of the interaction
networks involved in several key common biological pathways correlated
to HCC and sorafenib. Our findings should be considered as a “proof of
concept” to be further validated in follow-up studies for the
stratification of HCC patients towards the improvement of therapeutic
choices.