Introduction
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Breast cancer biology and the future of tailored therapies
J. Bergh1, P. Hall2, A. €
Ostman1 & R. Toftg
ard3
From the 1Department of Oncology-Pathology, Karolinska Institutet; 2Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet; and 3Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Keywords: breast cancer, cancer stem cells, novel therapies, tumor microenvironment.
Introduction
Breast cancer is the globally most common malig-
nancy amongst women. The incidence has
increased dramatically over the last decades, par-
ticularly in the developing world. In 1980, 600 000
women were diagnosed with breast cancer,
whereas 1.6 million received the same diagnosis
in 2010 [1]. On the basis of these figures, it is
obvious that preventive measurements are needed,
combined with novel therapy strategies based on
tumour biological characteristics.
The mortality from breast cancer has decreased by
around 30–40% since 1980s due to the use of
adjuvant therapies and early detection. Targeted
therapies such as trastuzumab (a monoclonal anti-
body that blocks HER2/neu receptor functions) and
other anti-HER2-based drugs like lapatinib, pert-
uzumab and TDM-1 have lately been in focus. These
drugs, in particular if used in combination together
with chemotherapy, improve outcome in the meta-
static setting. There is hope that improved use of
these and other similar drugs may ultimately result
in cure. The curative potential has already been
demonstrated in the adjuvant and neoadjuvant
settings. In the latter, histopathological remission
is obtained in more than 50% of the cases when used
in combination with chemotherapy.
At the June 2012 Nobel conference ‘Breast cancer;
progress and challenges in prevention, risk predic-
tion, tumour biology and treatment’, world-leading
experts gathered to discuss recent findings related
to breast cancer biology and treatment. In addition
to major support from the Nobel Assembly at
Karolinska Institutet, the meeting was also spon-
sored by the Swedish Research Council, the Swed-
ish Cancer Society, Journal of Internal Medicine
(JIM) and the Karolinska Institutet-funded BRECT
breast cancer research network.
Some of the major and important topics are
discussed in five review papers of this JIM issue.
102 ª 2013 The Association for the Publication of the Journal of Internal Medicine
doi: 10.1111/joim.12101
In this introductory paper, we address and intro-
duce each of them.
Host and tumour cell interactions
It is increasingly recognized that the tumour
microenvironment exerts important regulatory
functions that influence tumour growth and
metastasis. Two reviews in this JIM issue address
the complex roles of hypoxia and the importance of
activation of stromal cells at metastatic sites [2, 3].
The review by Rundqvist and Johnson describes
how hypoxia induces functional alterations in
various cells of the tumour microenvironment,
including macrophages, vascular cells and fibro-
blasts [2]. These responses affect metastasis
through multiple mechanisms, including altera-
tions in the paracrine signalling to malignant cells
and changes in the functional characteristics of the
vasculature or immune cells.
The classical ‘seed-and-soil’ hypothesis of cancer
metastasis emphasizes the importance of host cell–
tumour cell interactions in metastasis. These ideas
receive new support through a series of findings
outlining the importance of host cell activation in
metastatic seeding [3]. A number of recent exper-
imental studies suggest that the activation of such
‘pre-metastatic niches’ includes both recruitment
of bone marrow–derived cells and activation of
resident cells including fibroblast. Obviously, tar-
geting of these processes is a highly interesting
strategy for adjuvant cancer therapy.
Mammary stem cells and tumour initiating cells
Important progress in the characterization of nor-
mal tissue stem cells, and their progenitors, has
been made over the recent past. This is relevant
because the phenotype of breast cancer cells is
influenced both by the tumour cell of origin and the
presence of specific somatic genetic alterations,
including activation of oncogenes or inactivation of
 J. Bergh et al.
tumour suppressor genes. Moreover, the mainte-
nance and spread of breast tumours is proposed to
rely on a population(s) of tumour cells with self-
renewal capacity and presenting several similari-
ties to normal tissue stem cells.
Martinez and Huelsken review in this JIM issue the
present knowledge on the metastatic process and
its dependency on cancer stem cells [4]. Special
emphasis is put on the understanding of which
cancer cells are endowed with metastatic potential
and the key role exerted by extracellular matrix
(ECM) components in establishing cellular niches
supporting the growth of metastatic cancer cells.
Targeting such ECM proteins provides a new and
interesting alternative therapeutic strategy to curb
metastatic disease.
Treatment and diagnosis of breast cancer
Future breast cancer therapies will include
improved selection of drugs, dosage and schedul-
ing, based on a better understanding of breast
cancer biology. Tumour heterogeneity is likely one
of the most important factors limiting the efficacy
of present therapies as described by Hayes and
Paoletti [5]. Another emerging issue is the clinically
relevant disconcordance in marker expression
between primary tumours and metastatic lesions.
Endocrine therapies are cornerstones both in the
early management of breast cancer as well as for
recurrent disease [6]. More recently, new targets
have been identified including ‘mammalian target
of rapamycin’ (mTOR). Inhibitors of this target
together with endocrine therapies have demon-
strated added value. Endocrine therapies can also
be combined with anti-HER2-based therapies for
the subgroup of oestrogen receptor–positive dis-
ease which also display alteration of the HER2
pathway. The effect so far is inferior to that
obtained with the combined use of cytotoxic agents
and anti-HER2-based therapies.
During the metastatic spread, further genetic
changes occur and act together with the tumour
stroma. Monitoring the biology of metastatic dis-
ease is required for optimal treatment. Present
procedures include different types of radiological
investigations, including advanced functional
imaging techniques. The additional need of biop-
sies of metastatic disease is becoming recognized,
but the practical limitations are sometimes a
problem. Circulation tumour cells and cell-free
Introduction: Introduction to breast cancer reviews
tumour DNA are emerging as highly interesting
alternative sources of prognostic and response-
predictive information [5].
Future perspectives
Targeted therapies have improved breast cancer
patient survival, but still 5–20% of all breast cancer
patients die from the disease within 10 years of
initial diagnosis. At the same time, there is a large
number of systemically treated women who are in
no need of postsurgical adjuvant therapy. These
women thus only experience the acute and late
adverse health effects of systemic therapy. It is
therefore of outmost importance to identify better
prognostic markers and therapy predictors with the
potential of reducing under- and overtreatment.
From the reviews in this issue of JIM, we learn that
tumour heterogeneity induces therapy resistance
but that circulating tumour cells could be a novel
way to monitor carcinogenic evolution. It is also
recognized that to identify tumours that form
metastasis, appropriate functional assessment of
the primary disease is needed, that the microenvi-
ronment of the metastatic cells is of outmost
important and that hypoxia influences the meta-
static potential. Lastly, we learn that novel combi-
nations of drugs, including endocrine drugs and
drugs targeting mammalian target of rapamycin
(mTOR) inhibitors, can be a way to increase ther-
apeutic efficacy.
These reviews all point at the complexity of carci-
nogenesis and the need of translational research
efforts to identify markers of prognosis, therapy
response and resistance.
Conflict of interest statement
Bergh’s research groups has received research
grants from Astra-Zeneca (KI-AZ collaboration),
Amgen,Bayer, Roche and Sanofi-Aventis for clin-
ical studies including biopsy, gene expression and
PET studies to the Karolinska Institutet and
Karolinska University hospital, but no personal
payments.
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104 ª 2013 The Association for the Publication of the Journal of Internal Medicine
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Introduction: Introduction to breast cancer reviews
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€
Correspondence: Arne Ostman PhD, Professor of Molecular
Oncology, Department of Oncology-Pathology, Cancer Center
Karolinska, R8:03, Karolinska Institutet, SE-171 76 Stockholm,
Sweden.
(fax: +46-8-33 90 31; e-mail: Arne.Ostman@ki.se).
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