Biomedical Engineering Reference
In-Depth Information
to its ligand estrogen, consequently leading to the activation of
ER-regulated transcription in target genes. Therefore, agents that
block the action of estrogen may interfere with, or even prevent,
the growth of breast cancer cells. The selective estrogen receptor
modulators (SERMs) such as tamoxifen are developed to block the
action of estrogen in the breast tissue.
31
It has been well documented
over several decades that ER and likely PR contents are associated
with a favorable clinical outcome and predict benefit from endocrine
treatment in both early breast cancer and metastatic breast disease
(Chapter 5).
10
Human epidermal growth factor receptor 2 (HER2), encoded by
the
gene, activates multiple cellular signaling pathways that
are involved in the cellular proliferation and survival. It is a driving
factor in tumor progression and confers a more aggressive tumor
behavior and an unfavorable prognosis.
ERBB2
32
Overexpression and/or
amplification of the
gene predict response as well as benefit of
treatment with trastuzumab, a recombinant humanized monoclonal
antibody to the extracellular domain of HER2, in early and metastatic
breast cancer (Chapter 4).
HER2
33
Lapatinib, a duel kinase inhibitor of
HER2 and EGFR, is approved for use in the treatment of advanced or
metastatic HER2-positive breast cancer. Recently, trastuzumab has
been approved by the U.S. Food and Drug Administration (FDA) for
the treatment of metastatic HER2-overexpressing gastric cancer.
34
Therefore, ER/PR and HER2, the molecular determinants of tumor
growth and progression, are the direct drug targets and represent
the therapeutic biomarkers of treatments.
Over the last decade, small-molecule kinase inhibitors have
emerged as an effective treatment in cancer patients whose tumors
harbor genomic alterations such as gene mutation, amplification or
chromosomal translocation in the target kinases. The fusion gene
of
the c-ABL
proto-oncogene from chromosome 9 with
the breakpoint
cluster region
) on chromosome 22 (BCR-ABL fusion gene on
chromosome 22) is named as the Philadelphia chromosome (Ph+).
It encodes a constitutively active tyrosine kinase in chronic myel-
ogenous leukemia (CML), some acute lymphoblastic leukemia, and
acute myelogenous leukemia (Chapter 8). Patients with Ph+ disease
dramatically respond to the tyrosine kinase inhibitors targeting the
BCR-ABL enzyme such as imatinib, dasatinib or nilotinib. c-Kit or
CD117, encoded by the
(
BCR
gene, is a cytokine receptor expressed on
the cell membrane of hematopoietic stem cells and other cell types.
Kit
