Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

118 Applying Pharmacogenomics in Therapeutics
an EGFR mutation. However, the prevalence of EGFR mutations varies significantly
across ethnic groups, from 10% in the white population to more than 40% in Asian
populations (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). In Asian NSCLC
cancer patients who were nonsmokers or only light smokers, this percentage can
be as high as 60%. For NSCLC with adenocarcinoma histology, the frequency for
EGFR mutation is about 10–20%, whereas the rate for squamous histology is about
1–15%. It is therefore recommended to test EGFR mutations for all nonsquamous
lung cancers, regardless of clinical characteristics.
The majority of EGFR mutations are located in the tyrosine kinase domain. The
two most frequent EGFR-activating mutations, p.L858R point mutation in exon
21 and small deletions in exon 19 (Del19), are responsible for about 90% of cases
(Ladanyi and Pao 2008). The less common or rare mutations (a varying frequency
of 1–3%) include p.L861Q mutation, a missense mutation at codon 719 (p.G719X,
about 3%) resulting in the substitution of the glycine at amino acid position 719
by a cysteine, alanine, or serine, and in-frame insertion mutations in exon 20. For
patients with a known frequent mutation (Del19 and p.L858R), treatment with an
EGFR-TKI, such as erlotinib, gefitinib, or afatinib, is a standard first-line therapy,
and multiple phase III trials showed that EGFR-TKI treatment has improved objective
response rate (ORR), progression-free survival (PFS), and health-related quality
of life (HRQOL). However, the sensitivity to EGFR-TKI and PFS are globally lower
for patients with less frequent or rare EGFR mutations.
The use of advanced molecular profiling of EGFR mutation status for
patients with NSCLC to direct targeted therapy with the EGFR-TKIs significantly
improves the treatment of this disease. However, patients undergoing EGFR-TKI
treatments will eventually relapse by acquired resistance (progression after initial
benefit). Acquired resistance may arise from different mechanisms, including pharmacological,
biological, and evolutionary selection on molecularly diverse tumors.
Polymorphisms in the previously discussed drug transporters such as ABCB1
(1236T>C, 2677G>T/A, and 3435C>T) and BCRP (ABCG2, 421C>A) may be relevant
for the pharmacokinetics of the EGFR-TKIs. EGFR mutation heterogeneity
could also contribute to the relapse. The emergence of EGFR exon 20 p.T790M
mutation clones seems to be the most frequent mechanism for acquired resistance
(Pao et al. 2005). It seems that there is the presence of a minor subclone (about 1%)
of p.T790M mutation before treatment of EGFR-TKI is selected. Although patients
with the EGFR exon 20 p.T790M mutation are resistant to EGFR-TKI treatment,
the presence of this alteration predicts a favorable prognosis and indolent disease
course, compared to the absence of it after TKI failure. Mutation in the genes of
the downstream signaling cascade of the EGFR pathway is another mechanism
for acquired resistance of EGFR-TKIs. One example is the KRAS gene, which has
been implicated in the pathogenesis of several cancers. Mutations in the KRAS gene
result in a constitutively activated KRAS protein that continually triggers these
downstream signals. Although EGFR TKIs can block EGFR activation, they cannot
block the activity of the mutated KRAS protein. Thus, patients with KRAS mutations
tend to be resistant to erlotinib and gefitinib. KRAS mutations are more likely
found in adenocarcinoma patients who are smokers, and white patients, rather than
East Asians, and are prognostic for poor survival (Riely et al. 2009).