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

Clinical Applications of Pharmacogenomics in Cancer Therapy
167
4 discrete liver metastases up to 3 cm in size, and bulky retroperitoneal adenopathy.
Colonoscopy reveals a nonobstructing tumor 20 cm from the anal verge, biopsy of
which is read as adenocarcinoma.
Question: What genetic test should be considered for this patient at this time before
therapy is started?
Answer: Active K-RAS mutation test is recommended. Biopsy samples are sent for
K-RAS testing, and results indicate wild-type K-RAS.
EGFR Antagonist and Targeted Therapy for Cancer
Epidermal growth factor receptor (EGFR, HER1, or c-ErbB-1) is activated by the
homo- or heterodimerization that triggers autophosphorylation of the c-terminus
region of the tyrosine kinase domain and initiates the cascade of downstream signal
transduction leading to cell proliferation. Although EGFR is constitutively expressed
in many normal epithelial tissues, it is commonly overexpressed in many human cancers,
including those of the head, neck, colon, and rectum. Therefore, EGFR gene overexpression
is a strong PGx indicator for selecting and predicting response to EGFR
antagonists, such as EGFR blocking antibody cetuximab and panitumumab, and
EGFR TKIs afatinib, erlotinib, and gefitinib. 87 Certain mutation of EGFR in cancer
cells lead to enhanced EGFR tyrosine kinase activation even without ligand binding to
EGFR. Generally, those cancer cells are resistant to treatments of any EGFR antagonists,
such as cetuximab and panitumumab, which block EGFR binding to its ligands.
In many cases, the EGFR TKIs, such as afatinib, erlotinib, and gefitinib, improve the
clinical outcome in cancer patients with activating EGFR mutations (predominantly
in never-before smokers, females, and tumors with adenocarcinoma histology) that are
sensitive to these drugs. 8 Exon 19 deletions and the L858R point mutation are the two
most common mutations sensitive to either erlotinib or gefitinib treatment. In contrast,
T790M mutation and exon 20 insertion are commonly associated with lower response
or resistance to erlotinib or gefitinib treatment. 88
K-RAS is an oncogene that encodes a member of the small GTPase superfamily
that plays an important role in the signal transduction of EGFR. The oncogenic
mutations of the K-RAS gene lead to the accumulation of ras protein in the active
GTP-bound state, which activates the downstream signal transduction pathway of
EGFR without ligand binding. In addition to the mutations of the EGFR tyrosine
kinase domain, mutated forms of the K-RAS have been shown to be present in many
human tumors, including colon and lung cancers. Approximately 97% of K-RAS
active mutations seen in NSCLC or colorectal cancer patients involve somatic mutations
of codons 12 and 13, which are resistant to EGFR antagonists therapy, including
both anti-EGFR monoclonal antibodies (cetuximab and panitumumab) and EGFR
TKIs (afatinib, erlotinib, and gefitinib). 8,89 K-RAS RGQ kit is the US FDA-approved
testing kit for K-RAS mutations. Generally, K-RAS mutations and EGFR mutations
are mutually exclusive to each other. Unlike EGFR mutations that are predominant
in never-before smokers, K-RAS mutations are more likely found in adenocarcinoma
patients who are smokers, and usually it is an indicator of a poor prognosis for
NSCLC. 8,88,89