PHARMACOGENETICS AND BREAST PART 2

mutation in the cell cycle-checkpoint kinase gene (CHEK2) confer a small but
appreciably enhanced risk of breast cancer [16••]. CHEK2
encodes a cell-cycle checkpoint kinase and is implicated in
DNA repair processes involving BRCA1 and p53. The
1100delC mutation, a truncating variant of CHEK2 that
abrogates the kinase activity, occurs at a frequency of 1.1%
in healthy individuals. However, this variant is present in
5.1% of individuals with breast cancer families that do not
carry mutations in BRCA1 or BRCA2. This mutation results
in an approximately 2-fold increase of breast cancer risk in
women and a 10-fold increase of risk in men. In contrast, the
variant confers no increased cancer risk in carriers of BRCA1
or BRCA2 mutations.
The penetrance of BRCA1/BRCA2 mutations is modified by
other genetic and/or environmental factors. Identification of
such modifiers would help in facilitating more accurate risk
assessment in carriers who face difficult clinical choices
regarding prophylactic mastectomy and oophorectomy.
Candidate modifiers include genes with products that are
known to interact with BRCA1 and BRCA2 [17]. RAD51 is a
homolog of bacterial RecA, which is required for meiotic
and mitotic recombination and for recombinational repair of
double-strand DNA breaks. Both BRCA1 and BRCA2
interact with RAD51 [18,19]. The presence of an SNP in the
5'-untranslated region of RAD51 (135 G-C) increased breast
cancer risk by 4-fold among BRCA2 but not BRCA1 mutation
carriers [20•,21•]. It is possible that this SNP could affect the
mRNA stability and/or translation efficiency, leading to
altered RAD51 protein levels. The differential effect of
RAD51 polymorphism on BRCA1 versus BRCA2 mutation
carriers may relate to the different pathways by which
BRCA proteins function.
Predicting drug efficacy and toxicity
The study of large numbers of genes that influence drug
activity, toxicity and metabolism provides the opportunity
to customize drug treatments, thereby eliminating the
uncertainties of current cancer chemotherapy. Specifically,
genetic polymorphisms in genes responsible for metabolism
and disposition of drugs, transporters and targets of drugs
are being explored [22••].
The cytochrome P450 (CYP) system has been under study
for a considerable period of time for predicting drug
efficacy. CYP enzymes are members of a multiple gene
'superfamily'. These enzymes play an important role in
steroidogenesis and detoxification of xenobiotics, such as
polycyclic aromatic hydrocarbons, benzopyrene, arylamines
and heterocyclic amines. One CYP gene, CYP2D6, appears to
contribute to metabolism of many anticancer agents [23]. It
is believed that common SNPs in CYP2D6 impair the
activity of CYP2D6 and perhaps alter the pharmacokinetics
of anticancer drugs.
Glutathione S-transferases (GSTs) detoxify a variety of
carcinogens and cytotoxic drugs by catalyzing the
conjugation of a glutathione moiety to the substrate.
Individuals who are homozygous carriers of deletions in the
GSTM1, GSTT1 or GSTP1 genes may have a higher risk of
cancer of the breast and other sites due to their impaired
ability to metabolize and eliminate carcinogens
Most drugs interact with specific target proteins, such as
receptors, enzymes or proteins involved in, for example,
signal transduction and cell cycle control, for exerting their
effects. Polymorphisms in thee target genes can alter
sensitivity to the drugs. This interaction has been exploited
in the analysis of breast cancers to determine their suitability
for treatment with the recombinant humanized monoclonal
antibody trastuzumab (Herceptin) [27••], which brings
about the death of breast cancer cells by binding to HER2
receptors on their surface. The HER2 proto-oncogene
encodes a 185-kDa cell surface human epidermal growth
receptor 2 protein known as the HER2 protein or receptor
[28]. The gene is also known as HER2/neu, as it has
homology to the rat gene neu. Normal cells express a small
amount of HER2 protein, which is activated by
heterodimerization with HER1, HER3 and HER4 in a
complex with their ligands [29]. The HER2 gene is amplified
in 25 to 30% of breast cancers, leading to the expression of
HER2 proteins at abnormally high levels in cancer cells [30].
Women with breast cancers that overexpress HER2 have an
aggressive form of the disease with significantly shortened
disease-free survival and overall survival [29,31-33].
Treatment with trastuzumab is successful only in breast
cancers that overexpress HER2 receptor.
Fluoropyrimidine prodrugs (eg, capecitabine) are widely
used to treat solid tumors such as colorectal, breast, and
head and neck cancer. This drug needs to be activated in the
tumor to the active drug 5-fluorouracil (5-FU) by the enzyme
thymidine phosphorylase (TP), which is usually expressed
in higher amounts in tumors than in healthy tissue.
Normally,
85%
of
5-FU
is
broken
down
by
dihydropyrimidine dehydrogenase (DPD) in the liver, but
between 3 to 5% of the population have reduced DPD
activity and manifest more severe gastrointestinal and
hematological toxicity when treated with 5-FU. Reduced
DPD activity has been correlated to mutational inactivation
[34]. The ratio of TP to DPD expression (TP/DPD ratio)
appears to determine the level of 5-FU in the tumor, in
addition to its effectiveness. 5-FU inhibits tumor cell
proliferation by targeting thymidylate synthase (TS), an
enzyme that is required for de novo pyrimidine synthesis.
Multiple studies have demonstrated that TS mRNA and
protein levels are inversely related to clinical antitumor
response [35,36]. The expression of TS is controlled in part
by a polymorphism characterized by a multiple number of
tandem repeats of a 29-base pair sequence in the 5'-promoter
enhancer region (TSER) of the gene. Multiple in vivo studies
have demonstrated that increasing the number of repeats
leads to an increase in TS mRNA and protein levels
[37•,38•]. Together, these studies suggest that combined
genotyping and protein level estimation of TP, DPD and TS
genes might be useful in selecting patients who are likely to
tolerate and respond to 5-FU therapy.