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Shek et al. Cancer Drug Resist 2019;2:69-81 I http://dx.doi.org/10.20517/cdr.2018.20 Page 75

cycle. Frequent polymorphisms rs17849079 and rs7640662 within the PIK3CA gene (encoding p110a, the main
[46]
subunit of PI3K) occur in 10%-18% of patients with colorectal cancer and are known as “hotspot mutations” .
A recent meta-analysis confirmed that rs17849079 allele T and rs7640662 allele C predict poor objective
response rate, lower OS and PFS in patients with metastatic colorectal cancer, treated by cetuximab and
[47]
panitumumab . The PTEN gene, encoding phosphatase and tensin homolog (PTEN) protein is an inhibitor
of the PI3K/mTOR pathway, and is strongly linked to a number of cancers. Several studies have demonstrated
that PTEN single nucleotide polymorphisms (SNPs) rs701848 allele C, rs2735343 allele G and rs11202586 allele
[48]
T are correlated with increased risk of oesophageal squamous cell cancer and testicular germ cell tumours ,
however they have demonstrated no association with response to mAb treatment to date.

Like other tissues, tumours require adequate vascularisation to proliferate. Vascular endothelial growth
factor (VEGF) is a key signalling molecule in this process. The VEGF family consists of 5 members:
VEGF-A, placenta growth factor, VEGF-B, VEGF-C and VEGF-D, all of which signal through unique
receptors (VEGF receptors). There are three VEGF receptors, VEGFR1, VEGFR2 and VEGFR3, all of which
possess unique roles and tissue distribution. Due to its role in angiogenesis however, the majority of cancer
research has focused on VEGFR2 and to a lesser extent VEGFR3 for its role in lymphangiogenesis, a crucial
[49]
driver of cancer metastasis . Following VEGFR2 binding, Ras-ERK and PI3K-AKT pathways are activated
[50]
to stimulate angiogenesis, proliferation and survival . VEGF-A and VEGF-C are the key oncogenic drivers
[51]
within the VEGF family, stimulating angiogenesis and lymphangiogenesis respectively . Due to their
angiogenic role in tumour formation, the VEGF pathway has become a therapeutic target, as exemplified by
[52]
anti-VEGF mAbs such as bevacizumab and chemotherapeutic drugs Sunitinib and Sorafenib [Figure 3].
As with EGFR, VEGF genetic polymorphisms can influence individual response to anti-VEGF mAb
therapies. In 2008 Schneider and colleagues demonstrated that VEGFA polymorphisms were associated
[53]
with median OS for the treatment of metastatic breast cancer with bevacizumab . In particular, patients
with the VEGF rs699947 AA genotype, who were treated by combination of anti-VEGF bevacizumab and
paclitaxel chemotherapy had better treatment response and improved OS, as compared to patients treated
[53]
with paclitaxel only . In the case of metastatic colorectal cancer, patients with the rs833061 TT VEGF
genotype treated with bevacizumab in combination with folinic acid, fluorouracil and irinotecan showed a
reduced risk of PFS . In addition, SNPs rs699947 C>A and rs833061 C>T have both been shown to increase
[54]
the expression of VEGF protein, and may account for the genotype based differences in anti-VEGF mAb
response [55,56] .

Mutations in the RAS gene family also affect the response to bevacizumab treatment, where they are present
[58]
[57]
in 30% of all human cancers . In 2016, Fiala et al. reported that among 404 Caucasian patients with
metastatic colorectal cancer, those with the RAS gene KRAS G12A/V (rs121913529) had lower PFS and OS
comparing to patients with KRAS wild-type when treated with bevacizumab. In a group of bevacizumab
treated Asian patients with KRAS G12A/V (rs121913529) polymorphism, objective response rate was also
[59]
lower comparing to patients with wild type tumours . Another study showed that among 167 patients
who underwent resection of lung metastases for metastatic colorectal cancer, perioperative bevacizumab
[60]
was correlated with better recurrence and OS in those who had KRAS exon 2 codon 12 mutations . The
beneficial effect of bevacizumab in patients with a KRAS codon 12 mutation was speculated to be due to its
[61]
association with VEGF upregulation thus promoting angiogenesis . As an inhibitor of VEGF signalling,
[62]
bevacizumab may inhibit cancers that are reliant on VEGF mediated tumorigenesis . The findings relating
to treatment outcome eventually translated into clinical practice, with KRAS genotyping becoming an
important determinant of EGFR mAb therapy usage .
[63]

Influence of genetic polymorphisms on the efficacy of immune-checkpoint inhibitors
A new class of highly effective mAbs known as immune-checkpoint inhibitors have recently come into
use that target checkpoint proteins present on T cells. These cell receptors termed CTLA-4 and PD-1 are