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

164 Applying Pharmacogenomics in Therapeutics
Overexpression of the HER2 oncogene is correlated with a poor prognosis, increased
tumor growth and metastasis, and resistance to chemotherapeutic agents. 22 Assessment
of HER2 status by IHC or FISH is the standard for the evaluation of newly diagnosed
carcinomas of the breast. Trastuzumab, pertuzumab, ado- trastuzumab emtansine,
and lapatinib are HER2 antagonists approved for the treatment of HER2-positive
cancers. Several FDA-approved HER2 tests are available, including InSite HER2/
neu (CB11), HER2 FISH PharmDx kit, HercepTest kit, Spot-Light HER2 CISH kit,
Inform HER22 Dual ISH DNA Probe Cocktail, Pathway, and so on. Positive HER2
is evaluated by FISH or IHC with an average copy number of the HER2 gene > 6 or
a ratio of HER2 gene/chromosome 17 > 2.2 by FISH, or scored 3+ by IHC.
For patients with positive HER2/neu, there are currently four HER2 targeted
therapy regimens in the market: trastuzumab (Herceptin ® ), lapatinib (Tykerb ® ), pertuzumab
(Perjeta ® ), and ado-trastuzumab emtansine (Kadcyla ® ).
Trastuzumab (Herceptin) is a recombinant DNA-derived humanized monoclonal
antibody that selectively binds with high affinity to the extracellular domain of the
human EGFR 2 protein (HER2). Assessment of HER2 status by IHC or FISH is the
gold standard for the evaluation of newly diagnosed carcinomas of the breast. HER2
overexpression is an indicator for use of trastuzumab therapy. Trastuzumab has been
approved for monotherapy or combined therapy in the treatment of HER2-positive
metastatic breast cancer and for HER2-positive metastatic gastric or gastroesophagel
junction adenocarcinoma as it can improve OS and PFS in HER2-positive advanced
gastric cancer. 73,74
Lapatinib (Tykerb) is an oral dual tyrosine kinase inhibitor (TKI) that targets
EGFR and HER2. Lapatinib can inhibit HER2 activation via ligand-induced heterodimerization
or truncated HER2 receptors. Clinical studies have shown that
trastuzumab-refractory breast cancer patients respond well to lapatinib. The NCCN
lists lapatinib in combination with capecitabine as an option for trastuzumab-refractory
breast cancer patients. 75,76 Blackwell and colleagues demonstrated that trastuzumabrefractory
breast cancer patients responded to lapatinib, and lapatinib in combination
with trastuzumab significantly improve PFS compared with lapatinib alone. 77
In recent years, there have been more developments of newer HER2-targeted
therapies, such as pertuzumab and ado-trastuzumab emtansine. These new therapies
have provided more treatment options for patients with metastatic breast cancer.
Pertuzumab is an HER2/neu receptor antagonist that augments the antitumor
activity that complements the activity of trastuzumab (Herceptin). Pertuzumab binds
to a different binding region of the HER2 receptor compared with trastuzumab, and
thus pertuzumab needs to be used together with trastuzumab. Pertuzumab targets the
extracellular dimerization domain (subdomain II) of the human epidermal growth factor
receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization
of HER2 with other HER family members, including EGFR, HER3, and HER4. 78
As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two
major signal pathways: mitogen-activated protein kinase (MAPK) and phosphoinositide
3-kinase (PI3K). Inhibition of MAPK and PI3K signaling pathways can result
in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates
antibody-dependent cell-mediated cytotoxicity (ADCC). The drug’s antitumor activity
is significantly augmented when administered in combination with Herceptin.