Early breast cancer: A review - Cancer Therapy

Cancer Therapy Vol 6, page 463
Early breast cancer: A review
Review Article
463
Cancer Therapy Vol 6, 463-476, 2008
Kyriakos Kalogerakos 1, *, Chrisostomos Sofoudis 1 , Nikolaos Baltayiannis 2
1 Breast Unit Metaxa Cancer Hospital, Piraeus Greece
2 Department of Thoracic Surgery Metaxa Cancer Hospital, Piraeus, Greece.
__________________________________________________________________________________
*Correspondence: Kyriakos Kalogerakos, Metaxa Cancer Hospital, 51 Botasi, Piraeus, Greece; e-mail: ageliki@diagoras-travel.gr
Key words: Early breast cancer, early breast cancer diagnosis, early breast cancer treatment, minimally invasive procedures
Abbreviations: 5-fluorouracil, adriamycine, cyclophosphamide, (FAC); 5-fluorouracil, epirubicin, cyclophosphamide, (FEC); Advanced
Breast Biopsy Instrumentation system, (ABBI); American Joint Committee on Cancer, (AJCC); American Society of Clinical Oncology,
(ASCO); Aromatase inhibitors, (AIs) axillary lymph node dissection, (ALND); Axillary lymph node dissection, (ALND); breast
conserving surgery, (BCS); breast conserving therapy, (BCT); clinical breast examination, (CBE); cyclophosphamide, methotrexate, 5fluorouracil
, (CMF); ductal carcinoma in situ, (DCIS); Early Breast Cancer Trialists' Collaborative Group, (EBCTCG); estrogen
receptor, (ER); extensive intraductal carcinoma, (EIC); fine needle aspiration, (FNA); Focused Ultrasound Ablation, (FUA); Food and
Drug Administration, (FDA); Magnetic resonance imaging, (MRI); Minimally Invasive Breast Biopsy, (MIBB); progesterone receptor,
(PR); radiationtherapy, (RT); Radiofrequency Ablation, (RFA); selective estrogen receptor modulator, (SERM); sentinel lymph node
biopsy, (SLNB); sentinellymph node, (SLN); tumor, nodal, metastasis, (TNM)
Received: 2 July 2008; Revised: 4 August 2008
Accepted: 21 August 2008; electronically published: September 2008
Summary
Breast cancer remains a common disease throughout the world. The prognosis of early breast cancer is generally
favorable. Especially, ductal carcinoma in situ has been regarded as a non-life-threatening disease. Therefore, early
diagnosis and early onset of the treatment has been important. Early age at menarche, late age at first birth and late
age at menopause are related to breast cancer risk. Examination by mammography and ultrasonography is still the
most effective means of detection for premenopausal and postmenopausal women, respectively. Additionally, there
have been important advances in MRI, sentinel lymph node biopsy, breast-conserving surgery, partial breast
irradiation, neoadjuvant systemic therapy and adjuvant systemic therapy. Another approach is to treat primary
tumors without surgery. For this purpose, several new minimally invasive procedures, including radiofrequency
ablation, interstitial laser ablation, focused ultrasound ablation and cryotherapy, are currently under development
and may offer effective tumor management and provide treatment options that are psychologically and cosmetically
more acceptable to the patients than are traditional surgical therapies. Here we review new knowledge about early
breast cancer the last years.
I. Introduction
Breast cancer continues to be the most commonly
diagnosed cancer in women in the United States,
accounting for 26% of all female cancers (Jemal et al,
2006).
In 2007, approximately 178, 480 women and 2, 030
men will be diagnosed with invasive breast cancer and 40,
460 women and 480 men will die from the disease (Ries et
al, 1975-2000; American Cancer Society. Cancer Facts
and Figures 2004 and 2005).
Additional breast cancer is the most common cancer
amongst women in England and Wales: 38, 651 women
were diagnosed as having breast cancer in 2003. The most
common age at diagnosis was between 55 and 59 years,
although the median age was between 60 and 64 years
(Welsh Cancer Intelligence and Surveillance Unit
(WCISU), 2004; Office for National Statistics, 2005).
One-third of new breast cancer cases are aged 70
years or over. The likelihood of diagnosis increases with
age, doubling about every 10 years until the menopause,
when the rate of increase slows dramatically (Quinn et al,
2001, Mcpherson et al, 2000).
In Greece the incidence is more than 3000 per year
and the annual increase over the last 20 years has been 1.3
%. The disease is unusual before the age of 40, but
increases rapidly thereafter.
Although the incidence of breast cancer has been
increasing in Greece its mortality rate has been decreasing.
This decline in mortality could be due to widespread use
of mammography, advances in evaluation techniques and

effective adjuvant treatment. Despite this, approximately
1600 patients die from breast cancer every year in Greece.
TNM stages I, II and IIIA are the "early" stages of
invasive carcinoma and most of these tumors are
traditionally considered operable. More than 90% of breast
cancer diagnoses are made early in the disease. Early-stage
breast cancer is potentially curable with surgery, radiation
therapy and systemic therapy (Mirshahidi and Abraham,
2004).
In patients with early breast cancer who receive
appropriate treatment, 5-year survival rates are in excess
of 75%. This article is a review for early-stage breast
cancer.
II. Definition
The term "early breast cancer" refers to breast cancer
in stages 0, I and II at the time of diagnosis (AJCC, 2002).
Table 1. TNM classification Primary tumor (T).
Kalogerakos et al: Early breast cancer: A review
464
With stage 0, the cancer is non-invasive, meaning it
has not spread to surrounding normal tissue (sometimes
called carcinoma in-situ).
In stage I cancer, the tumor is two centimeters in size
or smaller and has not spread outside the breast. And, in
stage II, either:
• There is no tumor in the breast, but cancer is found
in the axillary lymph nodes (nodes under the arms); or,
• The tumor is two centimeters or smaller and has
spread to the axillary lymph nodes; or,
• The tumor is two-to-five centimeters and has
spread to the axillary lymph nodes; or,
• The tumor is larger than five centimeters and has
not spread to the axillary lymph nodes or,
• The number of lymph nodes involved with cancer
is not more than three (Table 1).
TX-Primary tumor cannot be assessed
T0-No evidence of primary tumor
Tis-Carcinoma in situ
• Tis (DCIS)-Intraductal carcinoma in situ
• Tis (LCIS)-Lobular carcinoma in situ
• Tis (Paget's)-Paget's disease of the nipple with no tumor; tumor-associated Paget's disease is
classified according to the size of the primary tumor
T1-Tumor 2 cm or less in greatest dimension
• T1mic-Microinvasion 0.1 cm or less in greatest dimension
• T1a-Tumor more than 0.1 but not more than 0.5 cm in greatest dimension
• T1b-Tumor more than 0.5 cm but not more than 1 cm in greatest dimension
• T1c-Tumor more than 1 cm but not more than 2 cm in greatest dimension
T2-Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3-Tumor more than 5 cm in greatest dimension
T4-Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below:
• T4a-Extension to chest wall
• T4b-Edema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules
confined to the same breast
• T4c-Both (T4a and T4b)
• T4d-Inflammatory carcinoma
Note: Dimpling of the skin, nipple retraction, or any other skin change except those described for T4b and T4d
may occur in T1-3 tumors without changing the classification.
Regional lymph nodes (N): Clinical classification
NX-Regional lymph nodes cannot be assessed (eg, previously removed)
N0-No regional lymph node metastases
N1-Metastasis to movable ipsilateral axillary lymph nodes(s)
N2-Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal
mammary nodes in the absence of evident axillary node metastases
• N2a-Metastasis to ipsilateral axillary lymph node(s) fixed to one another (matted) or to other
structures
• N2b-Metastasis only in clinically apparent (as detected by imaging studies [excluding
lymphoscintigraphy] or by clinical examination or grossly visible pathologically) ipsilateral internal mammary
nodes in the absence of evident axillary node metastases
N3-Metastasis to ipsilateral infraclavicular lymph node(s) with or without clinically evident axillary lymph
nodes, or in clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of clinically
evident axillary lymph node metastases, or metastasis in ipsilateral supraclavicular lymph nodes with or
without axillary or internal mammary nodal involvement
• N3a-Metastasis to ipsilateral infraclavicular lymph node(s)
• N3b-Metastasis to ipsilateral internal mammary lymph node(s) and clinically apparent axillary lymph
nodes
• N3c-Metastasis in ipsilateral supraclavicular lymph nodes with or without axillary or internal

Cancer Therapy Vol 6, page 465
mammary nodal involvement
Regional lymph nodes: Pathologic classification (pN)-Classification is based upon axillary lymph node
dissection (ALND) with or without sentinel lymph node dissection (SLND). Classification based solely on
SLND without ALND should be designated (sn) [eg, pN0 (i +) (sn)).
pNX-Regional lymph nodes cannot be assessed (eg, previously removed, or not removed for pathologic study)
pN0-No regional lymph node metastasis; no additional examination for isolated tumor cells (ITCs, defined as
single tumor cells or small clusters not greater than 0.2 mm, usually detected only by immunohistochemical or
molecular methods but which may be verified on hematoxylin and eosin (H&E) stains. ITCs do not usually
show evidence of malignant activity [eg, proliferation or stromal reaction])
• pN0 (i -)-No histologic nodal metastases and negative by immunohistochemistry (IHC)
• pN0 (i +)-No histologic nodal metastases but positive by IHC, with no cluster greater than 0.2 mm in
diameter
• pN0 (mol -)-No histologic nodal metastases and negative molecular findings (by reverse transcriptase
polymerase chain reaction, RT-PCR)
• pN0 (mol +)-No histologic nodal metastases, but positive molecular findings (by RT-PCR)
pN1-Metastasis in 1 to 3 ipsilateral axillary lymph node(s) and/or in internal mammary nodes with
microscopic disease detected by SLND but not clinically apparent
• pN1mi-Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm)
• pN1a-Metastasis in 1 to 3 axillary lymph nodes
• pN1b-Metastasis to internal mammary lymph nodes with microscopic disease detected by SLND but
not clinically apparent
• pN1c-Metastasis in 1 to 3 ipsilateral axillary lymph node(s) and in internal mammary nodes with
microscopic disease detected by SLND but not clinically apparent. If associated with more than 3 positive
axillary nodes, the internal mammary nodes are classified as N3b to reflect increased tumor burden.
pN2-Metastasis in 4 to 9 axillary lymph nodes or in clinically apparent internal mammary lymph nodes in the
absence of axillary lymph nodes
• pN2a-Metastases in 4 to 9 axillary lymph nodes (at least one tumor deposit >2 mm)
• pN2b-Metastasis in clinically apparent internal mammary lymph nodes in the absence of axillary
lymph nodes
pN3-Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically
apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary nodes; or
in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary
lymph nodes; or in ipsilateral supraclavicular lymph node(s)
• pN3a-Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0
mm), or metastasis to the infraclavicular lymph nodes
• pN3b-Metastasis in clinically apparent ipsilateral internal mammary lymph nodes in the presence of
one or more positive axillary nodes; or in more than three axillary lymph nodes with microscopic metastasis in
internal mammary lymph nodes detected by SLND but not clinically apparent
• pN3c-Metastasis in ipsilateral supraclavicular lymph node(s)
Distant metastasis (M)
MX-Distant metastasis cannot be assessed
M0-No distant metastasis
M1-Distant metastasis
STAGE GROUPINGS
Stage 0-Tis N0 M0
Stage I-T1 N0 M0 (including T1mic)
Stage IIA-T0 N1 M0; T1 N1 M0 (including T1mic); T2 N0 M0
Stage IIB-T2 N1 M0; T3 N0 M0
Stage IIIA-T0 N2 M0; T1 N2 M0 (including T1mic); T2 N2 M0; T3 N1 M0; T3 N2 M0
Stage IIIB-T4 Any N M0
Stage IIIC-Any T N3 M0
Stage IV-Any T Any N M1
III. Risk factors
Women with a family history of breast cancer should
obtain as much information as possible about those
relatives, including age at onset and type of cancer. The
risk of breast cancer development related to family history
increases with the number of affected relatives, specific
lineage and age at diagnosis. The younger the age at
465
diagnosis, the more likely that a genetic component may
be involved.
About 5-10% of breast cancer is thought to be linked
to changes (mutations)in certain genes. The most common
are those of the BRCA 1 and BRCA 2 genes. Women with
mutations in BRCA 1 or BRCA 2 have a high risk of

developing breast cancer, ovarian cancer and several other
types of cancer during their lifetimes.
However, most cases of breast cancer occur “by
chance”. The causes are still unknown, but there is
probably a combination of factors including lifestyle
factors, environmental factors and hormone factors.
A list of several risk factors for breast cancer are
shown in Table 2 (Mcpherson et al, 2000; Ceschi et al,
2007; Evans and Howell, 2007; Kiley and Hammond,
2007; Pruthi et al, 2007; Vitiello et al, 2007).
IV. Diagnosis
Early breast cancer does not usually cause pain.
When the cancer grows, it causes changes in the size
or shape of the breast: a lump or thickening may be
noticeable. In advanced cases the tumour can show signs
of ulceration of the skin and fixation to the chest wall and
in the worst cases large lymph nodes may be present
(Reeder, 2007; Albrand and Terret, 2008; Rolz-Cruz and
Kim, 2008).
If any of these symptoms appears a proper
investigation should be initiated. The “triple diagnosis”
includes clinical examination, mammography and/or
ultrasonography and fine-needle aspiration for cytology or
coreneedle biopsy for histopathological examination
(Soares and Johnson, 2007).
Mammography provides radiographic images of the
breasts with at least two sets of images, the mediolateral
oblique and cranial-caudal views. It remains the most
reliable and widely used method of breast cancer
screening. Radiation exposure to the breast and
surrounding structures is limited to one rad per breast
when performed with a modern mammography unit.
Ultrasonography, another imaging tool, uses sound waves
that pass through a gel-covered skin probe to determine
whether nodules or densities found on a mammogram or
physical examination are solid or cystic. The benefit of
total breast ultrasound continues to be studied and it is not
considered a replacement for screening mammography but
Figure 1. Mammography: Early cancer of the left breast.
Kalogerakos et al: Early breast cancer: A review
466
is an additional tool to further define abnormalities
detected on CBE or mammography (Figure 1).
Several studies have reported that mammographic
screening reduces breast cancer mortality by 23% (Vachon
et al, 2007).
Digital mammography employs detection software
that can highlight suspicious lesions in the breast not
initially seen by a radiologist.
Magnetic resonance imaging (MRI) is recommended
as a screening tool for women who have a 20%-25% or
greater increased lifetime risk of breast cancer. That
includes women with a strong family history of breast
cancer and women who are survivors of a previous
malignancy that was treated with chest radiation therapy
(Kaiser et al, 2008).
MRI is not routinely indicated for women with a
personal history of breast cancer, despite a 5%-10%
increase in risk of a second primary cancer in the first 10
years after diagnosis, as the use of adjuvant chemotherapy
and/or hormonal therapy significantly decreases overall
risk to less than 5% (Hazard and Hansen, 2007).
Table 2. Risk factors for breast cancer
Elderly
Developed country
Age at menarche before 11years
Age at menopause after 54 years
Age at first full pregnancy in early 40s
Family history
Previous benign disease (atypical hyperplasia)
Cancer in the other breast
Diet with high intake of saturated fat
Body mass index >35
Alcohol consumption (excessive intake)
Exposure to ionising radiation
Oral contraceptives
Hormone replacement therapy
Diethylstilbestrol (during pregnancy)

V. Minimal invasive diagnosis
For a long time, open surgical breast biopsy after
needlewire localization was considered to be the standard
diagnostic procedure for nonpalpable lesions. But now the
international guidelines state that at least 90% of breast
cancer patients should have received a diagnosis of
malignancy before entering the operating room
(Mastology EESo. EUSOMA Guidelines. 2005, 2006).
Several different percutaneous biopsy techniques are
applied to obtain material of nonpalpable lesions: fine
needle aspiration (FNA), large-core needle biopsy and
vacuumassisted needle biopsy.
FNA is a well-established tool for the evaluation of
palpable breast lumps but it can’t to distinguish between
invasive and in situ cancer and frequently we take
inadequate sampling and we have false-negative rates
(Wells, 1995).
These problems with the application of FNA have
led to the introduction of large-core needle biopsy for the
diagnosis of nonpalpable breast lesions.
Large-core needle biopsy is less operator-dependent
than FNA.
It allows identification of an invasive component
additional it facilitates the assessment of tumor grade and
provides sufficient material for additional
immunochemistry staining.
Diagnostic accuracy of large-core needle biopsy is
high 93-99%, whereas falsepositive results are extremely
rare (Verkooijen, 2002).
However, in some cases, the severity of the disease is
underestimated.
In up to 40%-50% of needle biopsies containing
high-risk lesions these are underestimated.
In an attempt to reduce disease underestimate rates,
vacuum-assisted breast biopsy was introduced in 1995.
With this technique, tissue samples are acquired by
using a single insertion of a probe (11-gauge) and vacuum
suction to retrieve core specimens. Several studies have
showed that vacuum-assisted needle biopsy can reduce the
high-risk and some advocate vacuum-assisted needle
biopsy (Kettritz et al, 2004).
Ultrasound guidance is the technique of first choice
for percutaneous biopsy and can be applied for image
guidance of FNA, large-core needle biopsy and
vacuumassisted needle biopsy.
But some nonpalpable lesions cannot be identified by
ultrasound. For these types of lesions, stereotaxis is used.
With stereotactic imaging, two digital images of the
targeted lesion are taken at +15o and -15o from the central
axis. This allows precise calculation of the coordinates of
the lesion. With this information, a biopsy needle can be
inserted into the lesion and while the biopsies are being
harvested, repeat stereotactic images can be taken to
confirm the position of the needle. Stereotactic image
guidance can be provided either by add-on devices, which
are attached to standard mammography units, or dedicated
prone biopsy tables. With the latter, the patient is
positioned in the prone position on a biopsy table while
her affected breast passes through an opening in the table
(Vlastos and Verkooijen, 2007).
Cancer Therapy Vol 6, page 467
467
Today a growing number of breast lesions, visible on
MRI only, are being detected, posing diagnostic
difficulties. Since the development of so-called “breast
biopsy coils” MRI-guided percutaneous large-core or
vacuum-assisted needle biopsy has become available in
some selected centers with success (Perlet et al, 2006).
VI. Staging
The TNM staging system was designed to be a useful
instrument in determining the prognosis of cancer patients
and in planning their treatment. The system is derived
from tumour size (T), lymph node status (N) and distant
metastasis (M). Clinical stage is based on all information,
including physical examination and imaging before
surgery. Pathological staging (pTNM) adds additional
information gained by examination of the tumour
microscopically by a pathologist.
A. Definition of pTNM
1. Primary tumour (T)
Tx, primary tumour cannot be assessed; T0, no
evidence of primary tumour; Tis, carcinoma in situ or
Paget disease of the nipple; T1, tumour 20 mm or less; T2,
tumour more than 20 mm but nor more than 50 mm; T3,
tumour more than 50 mm; T4, tumour of any size with
direct extension to chest wall or skin, or inflammatory
breast cancer.
2. Regional lymph nodes
N0, no node metastasis (includes cases with only
isolated tumour cells, or small clusters of cells, not more
than 0.2 mm); N1mi, micrometastasis (larger than 0.2 mm,
but none larger than 2 mm); N1, metastasis in 1-3
ipsilateral axillary node(s) and/or in ipsilateral internal
mammary nodes with microscopic metastasis detected by
sentinel lymph node dissection but not clinically apparent;
N2 metastasis in 4-9 ipsilateral axillary lymph nodes or in
clinically apparent internal mammary lymph node(s); N3,
metastasis in 10 or more ipsilateral axillary lymph nodes,
or in infra- or supraclavicular lymph nodes, or in both
ipsilateral axillary lymph nodes and clinically apparent
ipsilateral internal mammary lymph nodes. 13.
3. Distant metastasis (M)
M0, no distant metastasis; M1, presence of distant
metastasis (AJCC, 2002; Singletary et al, 2002,
Woodward et al, 2003) (Table 1).
B. Treatment
1. Surgical therapy
Breast cancer surgery has changed dramatically over
the past 20 years. With the emergence of breast conserving
therapy (BCT), many women now have the option of
preserving a cosmetically acceptable breast without
sacrificing survival (Veronesi et al, 2002).
BCT refers to surgical removal of the tumor without
removing excessive amounts of normal breast tissue. The
aim of BCT are to provide a cancer operation equivalent to
mastectomy and a cosmetically acceptable breast, with a
low rate of recurrence in the treated breast (Veronesi et al,

1990; Fisher et al, 2002). All of the available data,
including six randomized trials directly comparing BCT
with mastectomy and an overview of completed trials,
show equivalent survival with BCT as compared to
mastectomy (Early Breast Cancer Trialists’ Collaborative
Group, 2000).
The critical obstacle to widespread acceptance and
utilization of BCT is the risk of in-breast recurrence. Most
doctors advise against BCT and instead recommend
mastectomy if they estimate the risk of in breast
recurrence to be >10 to 15 percent over the succeeding 5
to 10 years, even after surgery and radiation. BCT
provides an acceptable alternative to mastectomy for
many, but is applicable to only 60 to 75 % of newly
diagnosed women.
The last years a growing number of women with
early-stage breast cancer seem to be choosing to have the
whole breast removed instead of just the cancerous lump,
doctors are reporting.
Now, a study of about 5, 500 women at the Mayo
Clinic in Rochester, Minn., shows that mastectomies are
on the rise (The Associated press, 2008).
The study was released Thursday 05.15.2008 by the
American Society of Clinical Oncology and will be
presented at the group's annual meeting later this month.
In the Mayo Clinic study, about 45 percent of breastcancer
patients chose mastectomies in 1997. That declined
to 30 percent in 2003, then started to rise. By 2006, 43
percent were opting for the more radical treatment
(www.azstarnet.com, 05.16.2008).
There are very few contraindications to BCT.
For most women, the choice of BCT versus
mastectomy can be a matter of personal preference.
Kalogerakos et al: Early breast cancer: A review
468
Absolute contraindications include pregnancy (first
or second trimester), diffuse suspicious calcifications,
previous radiation to the region and inability to achieve
negative margins (particularly with EIC-extensive
intraductal carcinoma). Relative contraindications include
two or more gross tumors (multicentric disease) in
different quadrants, tumor greater than 5 cm initially or
after neoadjuvant chemotherapy, large tumorbreast ratio
for cosmesis and collagen vascular disease (Daniel et al,
2008).
It’s truth that breast conserving surgery is not an
option for all women. If the tumour is !4cm, multifocal or
if radiotherapy has to be avoided, mastectomy is the
method of choice.
Regardless of the method used, an axillary lymph
node dissection is always mandatory.
The reason for this is that we know from several
studies that the axillary lymph node status is the most
important prognostic factor for recurrence and survival
(Moore and Kinne, 1997; Orr, 1999). Two different
operations of the axilla can be preformed.
Traditional axillary lymph node dissection or sentinel
lymph node biopsy (Figure 2).
The former has been the standard procedure for a
long time with additional side effects such as sensory
disturbances, lymphedema, pain, seroma formation, poorer
cosmetics and infections (Sener et al, 2001; Blanchard et
al, 2003; Reitsamer et al, 2003). The sentinel node biopsy
is by definition the first lymph node to receive lymphatic
drainage from a tumour. Today, the technique is
considered to be standard procedure (Bergqvist et al,
2008).
Figure 2. Sentinel lymph node biopsy (SLNB) is standard care for patients with early-stage breast cancer.

2. Minimally invasive procedures
Today breast conservation therapy has become the
treatment standard for early-stage breast cancer patients
and sentinel lymph node biopsy allows prediction of
axillary lymph node status without the need for axillary
lymph node dissection (Sener et al, 2001; Blanchard et al,
2003; Reitsamer et al, 2003; Albrand and Terret, 2008;
Bergqvist et al, 2008; Doughty, 2008).
The next challenge is to treat the primary tumor
without open surgery but with minimally invasive
procedures. Percutaneous tumor excision, radiofrequency
ablation (RFA), interstitial laser ablation, focused
ultrasound ablation (FUS) and cryotherapy provide
interesting alternatives to open breast surgery.
3. Percutaneous Stereotactic Excision
Percutaneous stereotactic biopsy techniques have
been used as a treatment option for excision of benign and
malignant breast lesions (Fine et al, 2003).
Stereotactic biopsy systems, including the Advanced
Breast Biopsy Instrumentation (ABBI) system (U.S.
Surgical, Norwalk, CT, http://www. ussurgical.com), other
vacuum-assisted core-sampling devices such as the
Mammotome (Ethicon, Cornelia, GA,
http://www.ethicon.com) and the Minimally Invasive
Breast Biopsy (MIBB; U.S. Surgical Corporation), were
developed and subsequently used in a percutaneous
excisional purpose; although the patients who treated with
these approaches were highly selected and conclusions
cannot be applied to all breast cancer patients.
4. Radiofrequency Ablation
Radiofrequency ablation has been used successfully
for the treatment of primary or metastatic tumors of
numerous organs, such as liver, lungs, bones, central
nervous system, pancreas, kidneys, or prostate
Radiofrequency Ablation destroys the tumor with heat
(Arciero and Sigurdson, 2008, Lehman and Landman,
2008; Steinke, 2008; White and D'Amico, 2008).
A radiofrequency probe (15-gauge) with RFA
electrodes is inserted in the tumor and an alternating highfrequency
electric current (400-500 kHz) is administered.
The heat that is generated affects the cell
membrane’s fluidity and the cytoskeleton proteins and
finally acts on the nuclear structure, resulting in the
interruption of cell replication. This finally leads to
irreversible tumor destruction, as tumor cells are more
susceptible to heat than are normal cells. The RFAtargeted
tumor volume depends on applied tension (up to
200 W). Under imaging guidance, the RFA probe is
inserted into the center of the lesion and a star-like array of
electrodes is deployed from the tip of the probe. At least 5
minutes are necessary to gradually reach the target
temperature (95°C). This temperature is maintained for 15
minutes to achieve complete ablation and is followed by a
1-minute cool-down period. Temperature is monitored
during the entire procedure by sensors (van Esser et al,
2007).
Several studies evaluated the use of RFA ablation in
the treatment of breast cancer.
Cancer Therapy Vol 6, page 469
469
The procedure was well-tolerated under local
anesthesia and sedation but the investigators don’t
proposed the RAF as an alternative to open surgery
because the patients have residual disease after application
of the intervention (Jeffrey et al, 1999; Singletary et al,
2002; Hayashi et al, 2003; Fornage et al, 2004).
5. Focused Ultrasound Ablation
Thermal tumor ablation has also been evaluated
using FUS. After localization of the tumor within the
breast, ultrasound can be focused and rapidly generate a
substantial increase in local temperatures of up to 90°C by
converting acoustic energy into heat. FUS ablation heats
the tumor and causes cell damage and tumor death (Chen
et al, 1999). FUS is based on a 1.5-MHz ultrasound
source. Tumor ablation is monitored through temperature
probes and skin monitors. Duration of FUS ablation is
usually 10 minutes. The major advantage of FUS over
other ablative techniques is that no skin incisions are
needed. However, tumors close to the skin may be treated
with less success and with such adverse effects as skin
burns.
6. Laser Ablation
Another technique currently being investigated for
local treatment of breast cancer is laser ablation. Laser
ablation is a technique that generates heat and
subsequently causes cell death and tumor destruction.
Laser energy is delivered directly to the target tumor
through a fiberoptic probe inserted
under imaging guidance. Several laser types have
been evaluated and used for thermal ablation: the Nd:YAG
laser (1064 d, 1, 320 nm), semiconductor diode laser (805
nID) and argon laser (488 and 514 nID).
Laser type 805 nID was used more because it is a
portable device and may be applied in tumors through
special needles. Laser ablation consists in delivering 2-2.5
W in 500 s (>1, 000 J for each fiber) on the tumor. The
size of tumor destruction can be increased with the use of
several fibers. Laser treatments may be performed under
imaging guidance (mammography, ultrasound, or MRI). A
target temperature of 80°C-100°C is generated during 15-
20 minutes to obtain tumor ablation.
Laser ablation for the treatment of early-stage breast
cancer has not been studied extensively, but some have
shown that small tumors can be ablated with negative
margins (Mumtaz et al, 1996). After technical
improvements, the success rate for complete tumor
ablation rose to 93% (Harms, 2001).
7. Cryotherapy
Cryotherapy was initially developed and used in the
treatment of nonoperable liver metastases from colorectal
cancers. Cryotherapy uses coldness to achieve tumor
destruction (Whitworth and Rewcastle, 2005). Energy is
produced by an external generator composed of an argon
or nitrogen freezing system and a helium heating system.
Cryosurgery involves the use of a freezing probe linked to
the generator. Several probes (up to seven) can be used
simultaneously to treat larger tumors, as thermal
conduction increases the volume of cooled tissue. The

probe is inserted in the center of the tumor under imaging
guidance (ultrasound or MRI) through a tiny incision.
Once the probe is positioned correctly,
an iceball is created at the needle tip. This iceball
destroys the tumor as well as 5-10 mm of additional breast
tissue surrounding the lesion. During each freeze cycle,
temperatures from -185°C to -70°C are obtained and
constantly monitored (Staren et al, 1997; Sabel et al, 2004;
Vlastos et al. 2004).
Currently, the U.S. Food and Drug Administration
has approved cryotherapy without resection as a treatment
option for core biopsyproven fibroadenomas.
For early-stage breast cancer (tumors less than 10-15
mm), cryotherapy is promising, as this technique can be
realized under local anesthesia (Bouchardy et al, 2003;
Caleffi et al, 2004).
8. Radiotherapy after surgery
Postoperative radiotherapy is known to substantially
reduce the risk of locoregional recurrence and improve
breast cancer mortality, both when given after mastectomy
and after breast-conserving surgery (EBTCG, 2005).
The meta-analysis by the EBCTCG included a total
of 7300 patients who underwent breast-conserving surgery
+/- postoperative radiotherapy towards the remaining
breast. The locoregional recurrence rate after 5 years was
7% versus 26% (reduction 19%) and 15 years breast
cancer mortality risks 30.5% versus 35.9% (reduction
5.4%) (EBTCG, 2005).
Patients have many fears in anticipating the radiation
experience. Fortunately for patients having BCT, the
treatment course is usually well tolerated and produces
limited side effects.
Of note, if systemic chemotherapy is indicated, it
will usually be completed before the initiation of
radiotherapy because there is no negative impact on local
control or disease-free survival and the chemotherapy may
benefit overall survival (Whelan et al, 2002).
Doses of 45 to 50 Gray (Gy) are typically given to
the whole breast, in daily, Monday-to-Friday fractions of
180 to 200 centiGray (cGy), over a 5-week period,
followed by a tumor bed boost of an additional 10 to 16
Gy over 1 to 2 weeks (Shelley et al, 2000; Owenet al,
2006).
Pathologic nodal status will determine whether
regional nodal groups also require concomitant adjuvant
radiotherapy in doses that are similar to those given to the
whole breast.
In discussing treatment with the patient, the clinician
should explain that treatments are typically given on a
linear accelerator and that there will be a treatment
planning session or simulation of about an hour before the
start, which will define the treatment fields and mark the
skin. Total daily treatment time usually averages 15 to 20
minutes. The treatments are not painful and the radiation
cannot be seen or felt. Radiotherapy is a local treatment
that works only where the beams are pointed. Breast
irradiation will not cause hair loss of the scalp, nausea, or
lowered immunity and it should not harm the heart, lungs,
or spinal cord. Reassure the patient that she will not be
radioactive, does not need to monitor physical proximity
Kalogerakos et al: Early breast cancer: A review
470
to others and need not take special precautions with
clothes, urine, or stool.
Typical side effects include skin reactions ranging
from mild redness, dryness and itching to less frequent
moist desquamation, ulceration and infection. All usually
heal well after treatment. The patient may also experience
occasional mild shooting pains in the treated breast and
axilla, as well as some fatigue, which is not usually related
to low blood counts. There is a low but long-term risk of
scarring or fibrosis (eg, fat necrosis) of the treated breast
and tumor bed, alteration of breast symmetry and
hyperpigmentation, telangiectasias, or altered skin texture
(Kissinet al, 1986, Meric et al, 2002).
Adding radiotherapy after surgery increases the risk
of lymphedema-especially following axillary lymph node
dissection (18%) as opposed to sentinel lymph node
dissection (10%)-and decreased range of motion of the
ipsilateral upper extremity (Meric et al, 2002).
Other potential side effects, such as neuropathy,
plexopathy, radiation pneumonitis, rib fracture, cardiac
events and mortality in women with left breast cancer and
risk of secondary primary malignancies, all average less
than 1%. There is no correlation to risk of contralateral
breast cancer (Bartelink et al, 2001; Recht et al, 2001).
In spite of the data and excellent tolerability of
treatment, more than 40% of women with early-stage
breast cancer still opt for mastectomy, despite long-term
local recurrence and survival rates comparable with those
for BCT. Up to 25% of women who undergo lumpectomy
do not proceed to radiation therapy (Recht et al, 2001).
According to the American Society of Clinical
Oncology (ASCO) guidelines postoperative radiotherapy
after mastectomy, is recommended to patients with
tumours >5cm regardless of lymph node status and to
patients with four or more positive lymph nodes (Recht et
al, 2001).
This recommendation is some what controversial, as
two Danish randomised studies have shown a survival
benefit from radiotherapy in patients with tumours

promising results in terms of delayed tumour recurrence
(Fisher et al, 1975).
Despite the fact that both studies had very short
follow-up times (18 and 27 months, respectively) adjuvant
chemotherapy was considered the treatment of choice for
many women in most developed countries.
The original regimen used was cyclophosphamide,
methotrexate, 5-fluorouracil (CMF). Thereafter, many
other regimes have been used.
According to the meta-analysis by EBCTCG,
adjuvant poly chemotherapy, consisting of either CMF, 5fluorouracil,
adriamycin, cyclophosphamide (FAC) or 5fluorouracil,
epirubicin, cyclophosphamide (FEC), reduces
both recurrence and mortality from breast cancer
(Bonadonna et al, 1976).
The absolute reduction in breast cancer mortality for
women

11. Endocrine therapy
Tamoxifen, a selective estrogen receptor modulator
(SERM), inhibits the growth of breast cancer cells by
competitive antagonism of estrogen at the ER. However,
its actions are complex and it also has partial estrogen
agonist activity. These agonist effects can be both
beneficial (eg, prevention of bone demineralization) and
detrimental (increased risk of uterine cancer and
thromboembolic events) (Lee et al, 2008). Several
overviews of randomised trials have shown reduced
mortality in the adjuvant setting. The latest Oxford
overview (15 years follow-up) confirmed a 31% reduction
in mortality in women with ER-positive disease who
received tamoxifen for five years, regardless of age,
menopausal status or nodal status and a 39% reduction in
the incidence of contralateral breast cancer (EBTCG,
2005; Albrand and Terret, 2008).
A number of potential adverse effects are associated
with the administration of tamoxifen. These include hot
flashes and vaginal discharge in the short-term and a longterm
increase in the risk of thromboembolic events, as
well as a two- to three-fold higher risk of endometrial
cancer and uterine sarcomas (Rutqvist et al, 1995; Cosman
and Lindsay, 1999; Benson and Pitsinis, 2003; Riggs and
Hartmann, 2003).
Several factors may contribute to tamoxifen
resistance in breast cancer, including variable expression
of estrogen receptor alpha and beta isoforms, interference
with binding of co-activators and co-repressors,
alternatively spliced ER mRNA variants and modulators
of ER expression such as epidermal growth factor (EGF)
and its receptor (EGFR1, also called HER1) as well as the
type 2 EGFR, also called HER2 (Lipton et al, 2005).
Emerging studies also suggest that relative resistance
to tamoxifen may be related to inheritance of certain drug
metabolizing CYP2D6 genotypes that are associated with
a reduced activation of tamoxifen to its active metabolite
endoxifen. However, at present, routine assay to identify
the CYP2D6 genotype as a means of selecting patients for
tamoxifen is not considered standard practice (Jin et al,
2005). Tamoxifen 20 mg daily is a standard adjuvant
treatment option for both premenopausal and
postmenopausal women with ER+ early breast cancer.
Until more data become available, the recommended
duration of therapy is five years.
Aromatase is an enzyme that naturally converts
oestrogen from androgen.
In premenopausal women, most of the oestrogen is
produced in the ovaries, but in postmenopausal women,
most oestrogen is synthesised in peripheral tissue from
conversion of androgens (Simpson, 2003).
Table 3. Aromatase inhibitors
Kalogerakos et al: Early breast cancer: A review
472
Aromatase inhibitors (AIs) markedly suppress
plasma estrogen levels in postmenopausal women by
inhibiting or inactivating aromatase, the enzyme
responsible for synthesizing estrogens from androgenic
substrates (Smith and Dowsett, 2003) (Table 3).
In contrast to tamoxifen, these compounds lack
partial agonist activity.
Several trials have investigated the effectiveness of
aromatase inhibitors in postmenopausal women with ERpositive,
early breast cancer. Regardless of whether it is
given “up front” or sequentially after tamoxifen an
improvement in treatment outcomes have been noted
(Coombes et al, 2004; Jakesz et al, 2005; Howell et al,
2005; Thurlimann et al, 2005).
The MA-17 trial compared letrozole versus placebo
following five years of tamoxifen (Goss et al, 2003).
The MA17 trial showed that the aromatase inhibitor
letrozole further decreased the risk of recurrence and
improved overall survival (OS) for node positive patients
when given as extended treatment after five years of
tamoxifen (Jemal et al, 2006). AIs are associated with an
increased incidence of musculoskeletal complaints,
although the prevalence of these symptoms is unclear.
Most published trials as well as data derived from patient
surveys suggest that as many as 44 to 47 percent of
women experience joint pain or stiffness while taking an
AI in the adjuvant setting (Crew et al, 2006).
In contrast to tamoxifen, which has estrogenic (ie,
protective) effects in the bones of postmenopausal women,
all AIs cause bone loss by lowering endogenous estrogen
levels.
The best way to prevent bone loss associated with
AIs is unclear. Guidelines from ASCO and others suggest
that women with T-scores lower than -2.5 should exercise
and receive calcium, vitamin D and a bisphosphonate; use
of a bisphosphonate is "optional" for women with bone
densities between -1.5 and -2.5 (Hillner et al, 2003; Perez
and Weilbaecher, 2006).
However, most endocrinologists recommend
pharmacologic therapy for postmenopausal women with
T-scores less than -2.0, regardless of risk factors for
fracture and with T-scores less than -1.5 if risk factors are
present.
In all of the trials, compared to tamoxifen alone, AIs
have been associated with a lower risk of venous
thromboembolic and ischemic cerebrovascular events. In
some but not all trials, AIs have also been associated with
an increase in the risk of ischemic cardiovascular disease
compared to tamoxifen, although the magnitude of the
excess risk appears to be small (Mouridsen, 2006;
Mouridsen et al, 2007).
Generation Steroidal (type 1) Nonsteroidal (type 2)
First (nonselective) - Aminoglutethimide
Second (selective) Formestane Fadrozole
Third (superselective) Exemestane (Aromasin)
Anastrozole (Arimidex)
Letrozole (Femara)

VII. Conclusion
Increased awareness among women and
improvement in diagnostic procedures have enabled
earlier and better detection of breast cancer.
Improvement in breast cancer treatment has
undoubtedly also increased the long-term survival of
patients as reflected by the improved overall survival
across all breast cancer stages.
The prognosis of breast cancer has become relatively
good, with current 10-year relative survival about 70% in
most western populations.
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