Metastasis of Breast Cancer

Breast cancer is the leading female cancer in Europe and in the USA
and amongst the cancer types with high incidence in the rest of the world.
the female population in industrialised countries. The incidence of breast
group. Metastasis, the spread of breast cancer to other locations in the
body, is the main reason that leads to the mortality in the patients. The past
decades have seen a significant progress in understanding the molecular
and cellular mechanisms of cancer metastasis and development of new
diagnostic, prognostic and predictive tools. Some of the new discoveries
have been translated into clinical practice. This book aims at providing
the current knowledge in the area of molecular and cellular basis of
breast cancer metastasis, biological factors that influence the metastatic
process, developments in the diagnosis of metastatic breast cancer, and
current thinking in the management of metastatic breast cancer.
Robert E. Mansel1, Oystein Fodstad2, and Wen G. Jiang1
Cancer derives from a collection of multiple genetic aberrations, and the
same can be said as to the development of metastasis. The metastatic characteristics,
which may be predisposed or acquired during the development
1Metastasis and Angiogenesis Research Group, Cardiff University School of Medicin
Heath Park, Cardiff CF14 4XN, UK; 2Michell Cancer Institute, University of South
Alabama, University of South Alabama, 307 N. University Blvd., MSB 2015, Mobile,
AL 36688, USA
In the UK and USA, approximately one in every ten women will contract
the disease in their lifetime and it is amongst the leading cause of death in
cancer increases with age and is generally peaked in the 50–60 age
or metastasis- related genes. The past decades have witnessed the identification
of an increasing number of such genes. New technologies, such as
differential display, microarrays, and other high-throughput technologies
have aided the discovery. Some of the key genes and genetic control
mechanisms are discussed by Samant et al. in chapter 2. Beyond the traditionally
recognised metastasis-related genes, some of the genes previously
known only linked to the development and initiation of breast cancer
have also shown to be involved in invasion and metastasis. One example,
the BRCA1 gene, is discussed by Li et al. in chapter 3.
The process of metastasis is collectively known as the metastatic
cascade, during which a number of steps have to be completed by breast
cancer cells in order to successfully establish a metastatic focus at a distant
location. The process, although intimately linked to genetic mechanisms,
is also orchestrated by the interaction between cancer cells and its
surrounding environment. The interaction between cancer cells and the
surrounding matrix is extensively discussed by Bracke et al. in chapter 4.
In addition, the chapter has indepth discussion of the role of cell motility
and invasion in the metastasic spread of breast cancer.
A number of cellular structures are known to participate in the control
ones include the cytoskeletal system, cell adhesion (both cell–cell and
Martin in chapter 5 and Shevde and King in chapter 6. The role of matrix
and interaction between cancer cells and extracellular matrix has also
been documented in chapter 4.
Both intrinsic and exogenous factors have important influence over the
metastatic potential of breast cancer cells. Three of these factors/complexes
(HGF) IGF-1, and cyclooxygenase-2 (COX-2), respectively HGF is one
of the typical examples that cancer cells can be regulated by exogenous
factors generated by other cell types than cancer cells. HGF, generated
mainly by stromal fibroblasts in breast tumours, can be activated by a
complex enzymatic cascade and ultimately acts on both cancer cells and
endothelial cells. The responses from the respective cell types lead to
increased metastatic potential and angiogenesis. Chapter 9, however, has
emphasised the impact and importance of the regulators of HGF, includeing
matriptases, HGF activator (HGFA), and the HGFA inhibitors which
work in orchestration in the activation and inactivation of pro-HGF. The
importance of the IGF-I axis in the biology of breast cancer and predicting
the clinical outcome have been discussed in chapter 10. The role of
Mansel, Fodstad, and Jiang
mechanisms by which cancer cells metastasise. Those well-established
cell–matrix), and matrix-related mechanisms. Two of the specific struchave
been discussed in chapters 9, 10, and 13 – hepatocyte growth factor
COX-2 in breast cancer has been hotly debated in recent years. In chapter
13, Mokbel et al. have discussed the role of COX-2 in the metabolism of
of the disease, is also governed by a number of genetic mechanisms,
tures, cell–cell adhesion and tight junctions, have been discussed by
arachidonic acid and prostaglandins, the biological role of COX-2 in
breast cancer both in vitro and in vivo, the clinical value of using COX-2
as a prognostic predictor, and ways to interfere COX-2 in breast cancer
therapies.
The metastatic spread of breast cancer cells follows two main routes:
the vascular and the lymphatic. The vascular route, which is also intimately
linked to the angiogenesis process, has been extensively documented in
the past decade in reviews and books. The current volume has a focus on
the lymphatic route of cancer spread. Recent development in the generation
of new lymphatic vessels, lymangiogenesis, has been documented
by Al-Rawi and Jiang in chapter 11. Novel lymphatic markers and
Goyal and Mansel have discussed nodal metastatis, focusing on sentinel
node metastasis and the implications in cancer treatment.
The role of oestrogen and oestrogen receptors in breast cancer
development has been very well established in the past decade. However,
the impact of the female hormone in the invasion and metastasis of breast
cancer is beginning to be dissected. In chapter 7, Hiscox et al. have discussed
the impact of the hormone, hormone receptor, and hormone resistance
in the invasion and . Links between hormone
resistance and aberration in cell adhesion complex and growth factor
signalling are being established and may have important implications in
the understanding of endocrine regulation and the metastatic cascade.
Mokbel et al. in chapter 8, in which the role of aromatase in the metabolism
of female hormones as well as the clinical and prognostic value
of the enzymes are discussed.
One of the main destinations for metastatic breast cancer cells in the
body is the bone. Bony metastasis is the leading metastatic event in clinical
breast cancer. Although much is yet to be learned in the biology of bone
metastasis, Siclari et al. (chapter 12) have extensively discussed the factors
secreted by breast cancer cells in the development of bone metastasis. In
number of new molecules have been documented to actively participate
in the bone metastasis, as discussed in chapter 12. For example, the CCN
family, interleukins (IL-8, IL-11, and IL-18) have been shown to play a
key part in the development of bone metastasis. These new discoveries may
also help in tailoring treatment of these debilitating metastases. Further to
these development in understanding the biology of bone metastasis, the
lymphangiogenic factors have also been documented. In chapter 17,
The other hormone-related enzyme, aromatase, has been documented by
addition to the well-known molecules such as PTHrP and RANKL, a
clinical front on the current methods of diagnosis and strategies of treatment
of bone metastasis from breast cancer have been given by Lipton
(chapter 20).
Prognosis and predictive factors for metastatic breast cancer have also
been a topic of discussion. While the clinical and pathological factors
have their clinical value and implications, recent years have witnessed
the rapid progress in searching for new markers including molecular
markers. In chapter 14, Münster et al. have provided a thorough review
of the traditional and latest factors that have been used in predicting and
profiling metastatic breast cancer. While the value of nodal involvement,
tumour size, tumour grade, age, histology, and proliferation markers have
held their value, the authors have documented the latest development in
bone marrow micrometastasis, Her-2, and uPA. Furthermore, the chapter
has also provided an updated view on the development of molecular
profiling including using DNA microarrays, gene pattern arrays, which
may hold fresh information in this important area of metastasis research.
In chapter 15, Schröder et al. have explored the exciting new horizon in
the diagnosis of metastatic breast cancer, molecular imaging. New
methods (e.g., PET and FDG-PET) and labelling techniques have been
explored. Recent work on labelling HER-2 and ER as imaging tool has
also been explored.
The role of micrometastasis in breast cancer metastasis has gained
increasing recognition in the past decade. Müller and Pantel (chapter 16)
have provided a current view of the methods and molecular markers used
in the detection of disseminating tumour cells in the blood of patients with
breast cancer. The recent development in analysing the disseminating
that tumour cells acquire the genetic changes relevant to their metastatic
capacity early in tumorigenesis, challenging the traditional view that
tumour cells acquire their metastatic genotype and phenotype late during
tumour development. Investigations into the disseminating cancer cells
in bone marrow and the blood have provided prognostic information and
may prove valuable in decision making in the clinic. In chapter 17, recent
development in sentinel node metastasis has been explored. Current
methods of detecting sentinel node and details of current studies have
been analysed. Critically, a model of training for performing sentinel node
biopsy has been suggested, pointing to an important aspect of supervised
training in the success in conducting sentinel node biopsies. The importance
of sentinel node in decision making, prognosis, and predicting
clinical outcome has also been discussed in chapters 14 and 18.
Management of metastatic breast cancer has been covered by Riker
(chapter 21), from surgical, chemotherapeutic, and hormonal aspects,
Mansel, Fodstad, and Jiang
Diagnosis of metastatic breast cancer has been a long-debated issue.
tumour cells in primary and in early-stage breast cancer have indicated
(chapter 18), Pwint and Leonard (chapter 19), and Geisler and Lønning
respectively, together with Lipton (chapter 20), who deals with the
diagnosis and management of the bony metastasis. In chapter 18, the pattern
of breast cancer metastasis has been overviewed. Most importantly,
possible surgical options to the difficult secondary lesions, such as those
seen in the liver, bones, brain, and lungs, have been documented. In
chemotherapy in dealing with metastatic breast cancer. Endocrine therapy
has been an important pillar in the management of breast cancer. In
chapter 20, the current strategy in the management of bone metastasis
has been documented, with emphasis on the use of biphosphonates and
radiotherapy. In chapter 21, Geisler and Lønning have comprehensively
reviewed the available endocrine therapies, ranging from ovarian suppression
option to the latest anti-hormone methods, in the management
emphasised by the authors. Although chemotherapy of breast cancer is
improved and targeted therapies have been introduced for the treatment
of breast cancer, the role of endocrine therapy within the adjuvant and
metastatic setting has not been weakened, as the authors stated. This is
aramatase inhibitors, tamoxifen, and other new anti-hormone modalities.
has been a challenge from biological
knowledge to this important area of breast cancer.
chapter 19, Leonard and Pwint have discussed the current strategies of
metastatic breast cancer in pre- and postmenopausal women have been
of metastatic breast cancer. Different strategies for the treatment of
clearly supported by the recent results from the large-scale studies of
research to clinical management. The current book brings a wealth of