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

Pharmacogenomics and Laboratory Medicine
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of breast cancer. Breast cancer is the most common invasive cancer in women
worldwide, representing about 22.9% of invasive cancer in women.
About 18–20% of breast cancers are positive for HER2 (human epidermal growth
factor receptor 2) amplification (Owens et al. 2004; Slamon et al. 1987; Yaziji et al.
2004). The HER2 gene encodes a cell surface receptor that can promote cell growth
and division upon stimulation of growth signals. Amplification of the HER2 gene
results in abnormally high levels of HER2 and increases the growth and spread of
breast cancer. Compared to HER2-negative breast cancer, HER2-positive breast cancer
tends to be much more aggressive and fast growing if untreated. Fortunately,
there are several treatments available for HER2-positive breast cancer. Trastuzumab
(Herceptin) is a monoclonal antibody that binds to HER2 and prevents cell growth
by blocking HER2 receptors (Baselga et al. 1998; Pegram et al. 1998). In addition,
trastuzumab can also stimulate the immune system to destroy cancer cells, and it is
now a standard treatment along with adjuvant chemotherapy in patients with metastatic
HER2-positive breast cancer after surgery, since this dramatically reduces the
risk of recurrence. Another drug, lapatinib, a small molecule dual tyrosine kinase
inhibitor for HER2 and EGFR pathways, is often given for advanced HER2-positive
breast cancer if trastuzumab fails. Kadcyla, which is a trastuzumab connected to a
drug called DM1 that interferes with cancer cell growth, is another drug that can be
given to HER2-positive breast cancer patients previously treated with trastuzumab
and taxanes. Pertuzumab, a monoclonal antibody that inhibits the dimerization of
HER2 with other HER receptors, is also used for late-stage HER2-positive breast
cancer in combination with trastuzumab and docetaxel.
Approximately 15% of all newly diagnosed breast cancers are HER2-positive,
which means that the tumors either have extra copies of the HER2 gene inside the
cell and/or high levels of the HER2 protein on cell surfaced. HER2-positive breast
cancer patients are most likely to benefit from HER2-targeted treatment, which substantially
improves survival. On the other hand, HER2-negative patients are unlikely
to benefit from HER2-targeted treatment, and these patients should be identified to
avoid side effects as well as costs associated with these expensive drugs. It is therefore
very important for the testing laboratories to provide high-quality testing to
ensure accurate reporting of HER2 status. In 2007, the American Society of Clinical
Oncology (ASCO) and the College of American Pathologists (CAP) jointly issued
a guideline to improve the accuracy and reporting of HER2 testing in patients with
invasive breast cancer, which was subsequently updated in 2013 (Wolff et al. 2007,
2013). The guideline recommends that HER2 status must be tested for all newly
diagnosed invasive breast cancers, including primary site and/or metastatic site,
to determine whether HER2-targeted treatment is an option. Currently, two FDAapproved
HER2 testing methods are used in the United States, including immunohistochemistry
(IHC) and in situ hybridization (ISH). The IHC HER2 test measures
the amount of HER2 protein on the cancer cell surface; the results of IHC test can
be: 0 (negative), 1+ (also negative), 2+ (equivocal), or 3+ (positive-HER2 overexpression).
The ISH analyzes the number of copies of the HER2 gene inside each tumor
cell. The original ISH method is based on fluorescence (also known as FISH). The
updated ASCO–CAP guideline also adds recommendations for a newer diagnostic
method known as bright-field ISH that evaluates the amplification of the HER2 gene