Breast Surgery A Companion to Specialist Surgical Practice

Oncoplastic procedures to allow breast conservation
93
­tumour location and relative size of breast. If either
of these two goals is not achievable, mastectomy is
often chosen as an alternative to BCS. The failure of
classical BCS techniques to offer solutions for chal-
lenging scenarios has stimulated the growth and
advancement of new techniques in breast surgery
during the past decade. The dichotomy between
extent of excision and cosmetic outcome has made
it evident that new surgical techniques need to be
developed to address the problems and shortfalls of
BCS, and accommodate the expanding indications
for BCS.
Oncoplastic surgery (OPS) has emerged as a new
approach to allow wide excisions for BCS without
compromising the natural shape of the breast. It is
based upon integrating plastic surgery techniques
with immediate reshaping of the breast together
with oncological surgery to excise the breast can-
cer. The conceptual idea of OPS is not new and its
­oncological efficacy in terms of margin status and re-
currence compares favourably to traditional BCS.1,2
The difference in the level of difficulty in perform-
ing various oncoplastic procedures has created
a dichotomy in oncoplastic surgery. Oncoplastic
techniques range from simple reshaping and
­mobilisation of breast tissue to more advanced
mammaplasty techniques that allow resection of up
to 50% of the breast volume. Variations in difficulty
and the need for advanced training for some OPS
techniques require a clear classification system of
oncoplastic techniques, which provides a systematic
approach that all breast surgeons can follow when
undertaking BCS.
Oncoplastic considerations
Selection criteria for oncoplasty
There are three elements that are important in the
identification of patients who would benefit from
an oncoplastic approach. The two factors already
­recognised as major indications for OPS are excision
volume and tumour location.3 The third ­additional
element is glandular density, a recently recognised
factor in the determination of the safety of major
breast reshaping. When considered together, these
three major elements provide a sound basis for
­determining when and what type of OPS to perform
and, more importantly, in reducing the guesswork
when performing BCS.
Volume
Excision volume compared to the total breast ­volume
is estimated preoperatively. Through ­systematic cor-
relation of specimen weights compared with tumour
size, an accurate preoperative estimation of exci-
sion volume can be achieved, once the tumour size
is known from preoperative imaging. The average
specimen from BCS should weigh between 20 and
40 g, and as a general rule 80 g of breast tissue is the
maximum weight that can be ­removed from a me-
dium-sized breast without ­resulting in deformity (see
Chapter 4).
OPS techniques allow for significantly greater
­excision volumes while preserving the natural
breast shape. Reshaping of the breast is based upon
rearrangement of the breast parenchyma to ­create
a homogeneous redistribution of volume loss. This
redistribution can be achieved easily though either
the advancement or rotation of breast tissue into
­excision defects. Another option is to harvest a
­latissimus dorsi ‘miniflap’ to fill in the lumpectomy
cavity (see Part 1 of this chapter).3
Tumour location
High-risk zones in the breast are more likely to be
followed by deformity after BCS when compared to
more forgiving locations.
One example is the ‘bird's beak’ deformity that is
classically seen during excision of tumours from the
lower pole of the breast (Fig. 6.5a). Other ­examples
of difficult areas include excision of a central ­tumour
(Fig. 6.5b) and removal of cancers from the upper
inner quadrant (Fig. 6.5c). Therefore, it is important
when planning the appropriate ­surgical approach to
determine the tumour location and the likely level
The upper outer quadrant of the breast is a
favourable location for large-volume excisions. In
this location, defects can readily be corrected by
the mobilisation of adjacent tissue. Excision from
less favourable locations such as the lower pole or
upper inner quadrants of the breast often results in
breast deformity.
The first element is excision volume, which is the
single most predictive factor for cosmetic surgical
outcome and potential for breast deformity. Studies
have suggested that once 10–20% of the breast
volume is excised there is a clear risk of deformity4
(see Chapter 4).

Chapter 6
94
of associated deformity. An oncoplastic atlas of
surgical techniques based on tumour ­location has
been developed. The atlas provides a specific surgi-
cal technique for each possible tumour location in
the breast.
Glandular characteristics and
breast density
Glandular density is evaluated both clinically and
radiographically. Although clinical examination
provides reliable information on density, mammo-
graphic evaluation is a more reproducible ­approach
for breast density determination. Breast density
­predicts the amount of fat in the breast and deter-
mines the ability to perform extensive breast un-
dermining and reshaping without complications.
Breast density can be classified into four categories
based on the Breast Imaging Reporting and Data
System (BI-RADS). The four categories comprise:
(1) fatty; (2) scattered fibroglandular; (3) heteroge-
neously dense; or (4) extremely dense breast tissue.5
A dense glandular breast (BI-RADS 3/4) can be
mobilised easily with undermining and advance-
ment of breast tissue into the excision cavity with-
out risk of necrosis. Low-density breast tissue with
a major fatty component (BI-RADS 1/2) has a much
higher risk of fat necrosis if extensive undermining
is performed. Undermining the breast from both
the skin and pectoralis fascia is a major require-
ment to perform level I OPS. A low breast density
means that either the amount of undermining from
the breast and skin during level I OPS should be
­limited, or a decision made to proceed with a level II
­option that requires limited skin undermining. Level
II procedures that require extensive skin undermin-
ing such as the round-block technique are likewise
not suitable for the patient with a predominantly
fatty breast.
Classification system
Complexity of surgical procedure:
a bi-level system
A new classification of OPS techniques has been
proposed based upon the relative level of surgical
difficulty. Level I techniques should be able to be
performed by all breast surgeons without specific
training in OPS. A level I approach includes skin
and glandular undermining, including the nipple–
areola complex (NAC), and NAC recentralisation
if nipple deviation is anticipated. Level II techniques
encompass more complex procedures that involve
skin excision and glandular mobilisation to allow
major volume resection. Level II techniques are de-
rived from breast reduction techniques and require
additional training.
The bi-level classification system lends itself to the
creation of a practical guide to OPS and provides
the necessary framework during surgical planning
to correctly select the most appropriate surgical
procedure for the patient (Table 6.3).
Figure 6.5  •  Deformities after breast-conserving surgery.
(a) Lower pole: bird's beak deformity. (b) Central tumour.
(c) Upper inner quadrant.
a
b
c

Oncoplastic procedures to allow breast conservation
95
If less than 20% of the breast volume is excised
then a level II approach is not usually required and
a level I procedure is usually adequate. Anticipation
that 20–50% of breast volume is to be excised or
the ­cancer is in a specific location will require a level
II procedure to produce a satisfactory ­cosmetic out-
come. Large-volume excisions require concurrent
skin excision to adequately reshape the skin envelope.
If the breast parenchyma is fatty in composition, it
may be risky to employ a level I technique if excis-
ing more than 10% of the breast volume. A superior
outcome is likely to be obtained in such ­patients by
selecting an appropriate level II procedure.
General considerations for all
OPS techniques
The approach to OPS includes careful patient se-
lection and starts with patient counselling. It is
important to stress to the patient that although
oncoplastic procedures can provide greater satisfac-
tion with a better final breast shape and in some
situations will avoid the need for mastectomy,
outcomes do vary. During the consultation period
patients need to be informed that OPS may result
in longer and multiple scars. The position of each
incision should be described in detail. The patient
should also be made aware of the possible asymme-
try that will follow from a level II OPS. Asymmetry
in volume is expected, but necessary to limit breast
distortion and deformity. The patient must be in-
formed that, in such circumstances, to achieve sym-
metry an immediate reduction of the contralateral
side can be performed either at the same time or
later as a second-stage procedure.
All oncoplastic procedures begin with preoperative
marking of the patient sitting upright or standing
prior to the induction of anaesthesia. Once marked,
the patient is carefully centred on the operating
room table and secured so that she can be moved
from the supine to the upright position during the
operation. The arms can be extended if any ax-
illary surgery is planned, or secured by the side if
no ­axillary ­surgery is required. Movement between
these positions ­allows optimisation of contralateral
breast symmetry and allows for optimal reshaping.
Level I oncoplastic
techniques
The step-by-step approach for
level I OPS
The driving force behind level I OPS is the ­ability
of all surgeons to adopt the following steps into
their surgical practice. There are six general steps
for level I OPS that begin with the skin incision
(1) ­followed by undermining of the skin (2) and
NAC (3). After completion of undermining, a
full-­thickness glandular excision incorporating the
cancer and a ­surrounding rim of normal breast
­tissue is performed from subcutaneous fat down
to pectoralis fascia (4). The glandular defect is
subsequently closed, following specimen X-ray to
demonstrate complete radiological excision, with
tissue re-­approximation (5). If required, an area in
the shape of a crescent bordering the areola is de-
epithelialised to reposition the NAC (6). If this is
not performed the NAC displaces towards the site
of excision and is no longer positioned in the centre
of the breast mound.
Incisions
The concepts of oncoplastic surgery are not based
on minimising incision length. Short incision lengths
limit mobilisation of the gland and do not allow
creation of adequate glandular flaps to fill ­excision
defects.
In our experience, OPS is not minimally invasive sur-
gery. The location of the incision is at the discretion
of the operating surgeon. In general, incisions should
allow for both en bloc excision of the cancer, without
Criteria
Level I
Level II
Maximum excision
volume ratio
20%
20–50%
Requirement of skin
excision for reshaping
No
Yes
Specific training in
reduction and mam-
maplasty techniques
No
Yes
Glandular characteristics
Dense
Dense or fatty
Table 6.3  •  Oncoplastic decision guide
Effective mobilisation of the gland is a key
component in achieving a natural breast shape.

Chapter 6
96
causing fragmentation of the specimen, and also allow
undermining of the surrounding breast tissue to fa-
cilitate reshaping. The general principle for placing
incisions is to follow Kraissl's lines of maximum resting
skin tension to limit visible scarring6 (see Chapter 4).
However, in many cases an incision away from the
cancer is possible, such as along the areola border with
radial extension towards the tumour in the axilla for
upper outer quadrant lesions, or in the inframammary
fold for cancers in the lower half of the breast.
Skin undermining
Extensive subcutaneous undermining ranging from
one-half to two-thirds of the breast envelope may be
required to facilitate glandular redistribution after
removal of the tumour (Fig. 6.6a). Aggressive under-
mining can free an entire quadrant from the overly-
ing skin envelope. In terms of technique, it is easier
to undermine a large area of skin before excising the
lesion. Skin undermining should be performed in
the plane between the breast tissue and subcutane-
ous fat and definition of this plan is enhanced by the
use of hydrodissection using saline containing 1 in
500,000 to 1 in a million adrenaline (see Chapter 5).
Although smoking does not prevent the comple-
tion of a safe level I oncoplasty, it decreases the total
area of skin that can be undermined safely. Patients
who smoke should be warned of the greater risk of
complications and advised to reduce or stop smok-
ing for as long as possible before and immediately
after surgery (see Chapter 5).
The area of undermining should be inversely propor-
tional to the number of risk factors present, but the
final factor in determining the amount of undermining
that is safe is the fat composition of the breast. Division
of the chest wall perforating blood vessels in a fatty
breast is much more of a problem, and to maintain
tissue vascularity and reduce the risk of postoperative
necrosis, a level II procedure, which involves direct
glandular excision and less skin undermining, should
be considered if extensive undermining is considered
necessary to close the defect.
Nipple–areola complex
undermining
Risk factors for vascular compromise should
be evaluated prior to performing extensive
undermining. Smoking, diabetes mellitus and
connective tissue disease are recognised as risk
factors to be taken into consideration prior to
planning the surgery to be performed.
Major NAC distortion is a common cause of
breast deformity.
a
b
c
Figure 6.6  •  Level I oncoplastic techniques: skin and
NAC undermining. (a) Extensive skin undermining. (b)
Wide excision from subcutaneous fat to muscle, then
NAC undermining. (c) Glandular flap re-approximation.

Oncoplastic procedures to allow breast conservation
97
Fibrosis after surgery creates tension on adjacent
tissue, which results in NAC deviation towards the
area of excision. Fortunately, NAC repositioning
can be performed easily with simple undermining
and this is a key component of both level I and II
OPS. The first step is to completely transect the
terminal ducts under the nipple and separate the
NAC from the underlying breast tissue. A width
of 0.5–1 cm of glandular tissue is generally left at-
tached to the nipple to ensure the integrity of its
vascular supply. This amount of subareolar tissue
prevents NAC necrosis and limits venous conges-
tion. Even if the nipple is undermined and the ducts
divided immediately under the skin in most women
(>90%), the nipple will survive. The level of NAC
sensitivity is reduced by extensive mobilisation and
undermining and patients should be warned of this.7
Tissue excision
The standard approach is to perform a full-thickness
excision from the subcutaneous fat underlying the
skin down to the pectoral fascia.
The breast parenchyma itself may be excised in a fu-
siform pattern oriented towards the NAC to ­facilitate
re-approximation of the remaining gland, although
this potentially increases the total volume of tissue ex-
cised. In general, excise only what is needed and use
the remainder to help fill the ­defect. Before closing
the defect, metal clips are placed on the ­lateral edges
(superior, inferior, medial and ­lateral) of the ­tissue
defect in the breast to guide future radiotherapy. For
­superficial or deep cancers in breasts with an ante-
rior posterior distance of >4 cm then full-­thickness
­excisions are not always required. Preoperative imag-
ing is valuable in planning such excisions.
Re-approximation of the
glandular defect
During BCS, breast tissue is either re-approximated
or left open allowing for the eventual formation of a
haematoma or seroma. Seroma formation, ­however,
does not always result in predictable ­long-term
­cosmetic results for larger volume ­excisions. Once
reabsorption of the seroma occurs, the seroma
­absorbs and the excision cavity contracts due to fi-
brosis and retraction of the surrounding tissue, cre-
ating a noticeable defect together with distortion,
which then results in NAC displacement. For this
reason, where there has been an extensive resec-
tion, redistribution of the remaining breast volume
to redistribute the loss is required. Tissue mobilised
from lateral portions of the remaining gland or
­recruited from the central part of the breast allows
the ­creation of glandular flaps that can be sutured
together to close the defect (Fig. 6.6c).
De-epithelialisation and NAC
repositioning
A major source of patient dissatisfaction after BCS
is the usatisfactory position of the NAC ­because
it is deviated towards the excision site. This is
likely to happen after any extensive volume resec-
tion. NAC repositioning is exceedingly difficult
after ­radiotherapy, so immediate recentralisation
is ­advised and the need to recentralise the NAC
should be anticipated during the operation to resect
the cancer and should be performed then.
Avoiding NAC displacement is a key element for
both level I and II OPS. The NAC is repositioned
to adjust for both the anticipated deviation of the
nipple and the new shape of the breast. A crescentic
area of periareolar skin opposite the excision defect
is de-epithelialised (Fig. 6.7a–c). De-epithelialisation
can be achieved using a scalpel blade or fine scis-
sors. This technique is simple and safe and used
systematically in aesthetic surgery of the breast.
The vascular supply of the NAC after its separation
from the gland and de-epithelialisation is based on
the vasculature from the dermal plexus and this is
not compromised by careful de-epithelialisation.8
Level II oncoplastic surgery
Introduction
The major consideration when choosing the onco-
plastic technique to be used is the extent of ­excision
volume. A level I approach is suitable for excision
volumes less than 20% of the entire gland. The re-
sulting glandular defect can usually be filled by ad-
vancement of adjacent tissue. Immediate ­lipofilling in
Full-thickness excision ensures free anterior and
posterior margins, leaving only the lateral margins in
question (Fig. 6.6b).

Chapter 6
98
addition to tissue advancement adds extra ­flexibility
to the level I approach. Level II techniques are
generally reserved for situations that require major
volume excisions of between 20% and 50%.
To simplify the selection of a level II OPS tech-
nique, an atlas has been devised based on tumour
location. This atlas does not contain an exhaustive
list of options, but provides one or two options for
each tumour location.
Atlas principles
The concept of the oncoplastic atlas is based ­primarily
on tumour location. Initially used only for lower
pole tumours, OPS has evolved to allow ­resection
of breast lesions located almost anywhere in the
breast. Different mammaplasty techniques have been
adapted for specific locations in the breast.9
The superior pedicle reduction mammaplasty is a
model for the description of all mammaplasty tech-
niques. Schematically rotating the NAC on a pedicle
based directly opposite the site of tumour excision
allows the application of this technique for a variety
of tumour locations. These procedures are listed in
an anticlockwise direction and described for the left
breast.
Level II OPS will generally result in a smaller breast
that is rounder and higher on the chest wall than the
contralateral breast, thus there is a need for a contra-
lateral symmetrisation and the necessity to discuss
this with the patient prior to the excision. Either im-
mediate or delayed symmetrisation can be performed,
Figure 6.7  •  Level I oncoplastic techniques: NAC
recentralisation. (a) De-epithelialisation opposite
the tumour bed. (b) NAC recentralisation. (c)
Intraoperative result (upper outer quadrant resection).
Aa
b
c

Oncoplastic procedures to allow breast conservation
99
depending on the amount of tissue resected and the
desire of the patient. In a recent series of 175 women
having an oncoplastic breast-conserving procedure,
a contralateral breast reduction was performed in
25% of patients (19% during the initial operation
and 6% as a secondary procedure). A higher rate of
contralateral surgery was performed in patients who
had an inverted-T mammaplasty (50% vs. 14% with
other techniques; P<0.001).10
Lower pole location (4–7 o'clock)
General principles
The lower pole of the breast was the first location
recognised to be at high risk of deformity following
BCS.1 Removal of tissue from the 6 o'clock position
results in retraction of the skin and downward devi-
ation of the NAC, producing what is known as the
‘bird's beak’ deformity, which results in a low level
of patient satisfaction. A superior pedicle mam-
maplasty can permit large-volume excision of the
lower pole without causing NAC deviation and has
the added benefit of breast reshaping and elevation.
Techniques
‘Standard’ superior pedicle mammaplasty with
inverted-T scar (Fig. 6.8a–e)
The superior pedicle mammaplasty technique that is
in routine use involves using the inverted-T and peri-
areolar scars as utilised in most breast ­reductions.11
The procedure begins with the de-epithelialisation of
the area surrounding the NAC. Once completed, the
NAC is dissected away from the underlying breast
tissue. A superior pedicle of dermoglandular tissue is
preserved to provide the NAC with a blood supply.
The inframammary incision is then completed,
followed by wide undermining of the breast tissue
from the pectoral fascia, which can be preserved.
The undermining starts inferiorly and proceeds su-
periorly beneath the tumour while encompassing
the medial and lateral aspects of the breast as well
as the NAC. The tumour is removed en bloc with a
wide margin of normal breast tissue and overlying
skin as determined by the preoperative marking.
As for all BCS, the goal of the excision is to ­obtain
at least a 1-cm macroscopic margin of normal ­tissue in
order to ensure free microscopic margins. Mobilisation
a
b
c
d
e
Figure 6.8  •  Level II oncoplastic techniques for lower pole breast cancers: superior pedicle mammaplasty. (a) Treatment
planning: superior pedicle mammaplasty and contralateral symmetrisation. (b) Superior pedicle de-epithelialised.
Submammary fold incision. (c) Superior pedicle elevated. Wide excision of tumour and surrounding tissues. (d) Breast
reshaping. (e) Result.

Chapter 6
100
of the breast tissue from the pectoralis fascia allows for
palpation of both the deep and superficial surfaces of
the tumour, which improves the ability of the surgeon
to obtain clear margins. The breast tissue is remodelled
after the resection is completed. Remodelling incorpo-
rates the ­re-approximation of the medial and lateral
glandular columns towards the midline to fill in the de-
fect, followed by NAC recentralisation. All tissues ex-
cised should be weighed, as this provides a guide to the
amount of tissue to be excised in any ­contralateral re-
duction procedure. As a general rule the resection of the
cancer-bearing breast should be 10–20% less than ex-
cised from the opposite breast to allow for shrinkage of
the treated breast following whole-breast radiotherapy.
Results from excision of ductal carcinoma in situ at the
lower pole of the left breast are shown in Fig. 6.9a and b.
The result 2 years after operation is shown in Fig. 6.9c.
Vertical mammaplasty (Lejour/Lassus)
One modification to the technique to excise lower
quadrant tumours is to use the vertical-scar mamma-
plasty described by Lejour12 and Lassus.13 The site and
volume of excision are identical to the inverted-T scar,
but this approach avoids the submammary scar. In
general, T-shaped reductions work best in the largest
breasts and vertical scar ­reductions in smaller breasts.
Lower inner quadrant (7–9 o'clock)
General principles
Standard superior pedicle mammaplasty described for
tumours located at the 6 o'clock position can be ex-
tended to 7 o'clock. However, adaptation for tumours
located more medially, between 7 and 8 o'clock, is
more difficult and requires a novel level II technique.
Technique
V mammaplasty
This procedure involves excising a pyramidal section
of skin and underlying breast tissue with the base lo-
cated in the submammary fold and the apex at the
border of the areola. This skin and underlying breast
tissue are removed en bloc down to the pectoral fas-
cia. An incision is then made along the inframammary
fold and developed starting at the medial aspect of
the base of resection moving towards the anterior ax-
illary line and taken as far as necessary to perform
adequate mobilisation of the breast tissue laterally.
The lower pole of the breast is then mobilised off the
pectoralis fascia medially and laterally for use as an
­advancement flap to fill the defect. Volume replace-
ment is thus achieved through the advancement of the
gland from the remaining lower medial and lateral as-
pects of the breast. The NAC is then recentralised on
a de-epithelialised superior lateral pedicle.14
Upper inner quadrant
(10–11 o'clock)
General principles
Special caution is needed when considering BCS
for lesions in the upper inner aspect of the breast.
Figure 6.9  •  Level II technique for a 6-cm ductal
carcinoma in situ of the lower pole of the left breast.
Wide excision and postoperative radiotherapy.
(a,b) Preoperative. (c) Two years postoperation.
a
b
c

Oncoplastic procedures to allow breast conservation
101
A wide excision in this location can have a signifi-
cant impact on the overall quality of the breast shape
by distorting the visible breast line known as the ‘dé-
colleté’. This represents the visible area of the breast.
For moderate resections, level I techniques can be uti-
lised safely and combined with immediate ­lipofilling
to achieve a very smooth final contour. For more ex-
tensive excisions, the ability and likelihood of being
able to preserve the natural breast shape should be
discussed with the patient. Standard level II oncoplas-
tic procedures that reliably address the specific limita-
tions of BCS at this troublesome location are limited.
Silverstein and colleagues have described an effective
OPS procedure to address the upper inner quadrant.
Their approach utilises a batwing excision pattern.15
Silverstein et al.'s OPS solution is innovative but ex-
cises tissue in excess of that which is required, leaves
a large scar and, as described, removes pectoral fascia
as well as skin. Immediate lipofilling may offer the
best solution at present to this difficult area, combined
with mobilisation and closure of the defect.
Upper pole (11–1 o'clock)
General principles
Lesions located at the 12 o'clock position can be
excised widely followed by volume redistribution
of tissue from a central location. Access to lesions
in this location of the breast is accomplished either
using an inferior pedicle or round-block mamma-
plasty approach. The inferior pedicle mammaplasty
is commonly performed in the USA as a breast
­reduction technique and utilises an inverted-T scar
pattern.16 A round-block approach, on the other
hand, is more technically challenging when ­trying
to achieve the desired breast shape. These two tech-
niques are used extensively for breast reduction,
with low complication rates and durable results.
They can be applied for wide excision of upper pole
tumours while preserving a patient's natural breast
shape. There are dangers with this technique when
trying to preserve breast tissue superior to the ­nipple
to advance into the defect. So-called ‘bottoming out’
is a problem with inferior mammaplasty techniques.
Techniques
Inferior pedicle mammaplasty
The skin markings are identical to those described
for the superior pedicle reduction. The resection,
however, is located in the upper pole, hence the
­vascular supply of the NAC is based on its inferior
and posterior glandular attachments. The excision of
the cancer is performed through an incision placed
within the skin to be removed. Once the cancer has
been excised and the specimen X-ray shows complete
radiological excision, the inferior pedicle is de-epithe-
lialised and advanced upwards towards the excision
defect to achieve volume redistribution. Resection of
the breast tissue is performed in the inner and outer
lower quadrants to optimise the breast shape.
Round-block mammaplasty
The round-block mammaplasty utilises a periareolar
incision and was originally described by Benelli.17,18
The procedure starts by making two concentric peri-
areolar incisions, followed by ­de-­epithelialisation of
the intervening skin. The outer edge of de-­epithelialised
skin is incised and the ­entire skin envelope can then be
undermined to allow access to the tumour. The NAC
remains vascularised through its posterior glandular
base. Resection of the lesion from the subcutaneous
tissue down to the pectoralis fascia is performed and
this results in the formation of an external and inter-
nal glandular flap. The flaps are then mobilised off the
pectoralis fascia and advanced towards each other to
eliminate the excision defect. The two incisions are
then approximated, resulting in a periareolar scar.
Although the round-block mammaplasty has been
used mainly for upper pole tumours, it is a versatile
technique that can be easily adapted for tumours in
any location of the breast. The round-block technique
is not a method of breast reduction favoured by most
breast surgeons because it has limitations. In general,
there are alternative options to the round-block tech-
nique so, although some surgeons use it widely, others
use it rarely, if ever. Given its lack of universal favour,
this suggests the technique has its limitations.
Upper outer quadrant (1–3 o'clock;
Fig. 6.10a–c)
General principles
In the upper outer quadrant, large lesions can usu-
ally be excised with standard BCS without causing
deformity. However, resection of greater than 20%
of the breast volume will result in retraction of the
overlying skin with NAC displacement towards the
excision site. A result of a patient with a T3 can-
cer treated by neoadjuvant chemotherapy and wide

Chapter 6
102
­excision with mammaplasty is shown in Fig. 6.11a–d.
Level II OPS can be utilised to increase resection
possibilities while limiting deformity risk in this for-
giving region of the breast.
Techniques
Fusiform mammaplasty
A large portion of the upper outer quadrant can be
excised utilising a fusiform skin excision ­pattern
oriented in a radial direction from the NAC to-
wards the axilla, similar to a quadrantectomy.19,20
After wide excision, the reshaping is performed by
­mobilising the lateral and central gland into the
cavity and suturing it together. Central gland ad-
vancement is accomplished easily following NAC
undermining. Complete detachment of the retroare-
olar gland from the NAC enables the central part of
the gland to be available for volume redistribution
without compromise of NAC vascularity. Once the
defect is eliminated, the NAC is placed in its opti-
mal position, at the centre of the new breast mound.
The area of glandular ­excision directly follows the
skin excision. Additional glandular excision can be
­accomplished to remove almost the entire quadrant,
depending on tumour size and the amount of tissue
required to be removed to obtain clear margins.
Superior pedicled therapeutic mammaplasty
Given the increasing use of superomedial pedicles
in breast reduction surgery, tissue that is normally
removed from the lower breast can be kept alive on
a superomedial pedicle and rotated into the upper
outer quadrant. To be successful, care is needed to
maintain a wide base to the pedicle and thus main-
tain a good blood supply to the whole of the tissue
to be rotated.
Lower outer quadrant (4–5 o'clock)
General principles
A large-volume resection of the lower outer quad-
rant leaves a deformity similar to a bird's beak. As
for lower inner pole lesions, the inverted-T mamma-
plasty does not always ‘fit’ well for excisions within
this quadrant. One option is a J-type mammaplasty
described by Gasperoni et al.21
Techniques
J mammaplasty (Gasperoni)
The first incision begins at the medial edge of
the de-epithelialised periareolar area and then
gently curves upwards with a concavity to the
­inframammary crease. The second incision starts at
the lateral border of the de-epithelialised zone and
follows a similar pattern. The parenchymal exci-
sion then follows the skin pattern in the shape of
the letter J. The NAC remains vascularised on a de-
epithelialised superior pedicle and is detached from
the retroareolar gland. Lateral and central breast
a
b
c
Figure 6.10  •  Level II oncoplastic techniques for
upper outer quadrant breast cancers. (a) Treatment
planning: wide resection and NAC de-epithelialisation.
(b) Resection. (c) Breast reshaping and contralateral
symmetrisation.

Oncoplastic procedures to allow breast conservation
103
tissue can then be recruited into the excision defect
to achieve an equitable redistribution of remaining
breast volume.
Secondary pedicles
An alternative is to excise the cancer, leaving the
skin intact through the incision selected for reduc-
ing the breast – be that a T-shaped or vertical scar.
The skin that would normally be removed, is de-­
epithelialised and using primary pedicles attached
to the nipple–areola complex or secondary pedicles
attached to the inframammary fold, the defect is
closed.
Retroareolar location
General principles
Subareolar breast cancers are candidates for BCS.
However, superficial subareolar tumours are
­associated with a risk of NAC involvement ap-
proaching 50%.22 Such cases require en bloc re-
moval of the NAC with the tumour. This results
in a ‘flattened breast’ or ‘shark-bite’ deformity and
poor cosmetic outcome unless techniques are used
to avoid this. If the patient has a glandular breast
that allows wide undermining for reshaping, a level
I OPS is a reasonable option.
Level II mammaplasty techniques are reserved for
patients with ptosis or fatty breasts or for patients
for whom excision of more than 20% of the breast
volume is required. There are a number of mam-
maplasty approaches that can be chosen for the
centrally located lesion. They include the inverted-T
mammaplasty with resection of the NAC, a modi-
fied Lejour or J pattern with NAC excision or a
Grisotti flap (see Chapter 4). The latter offers the
advantage of allowing for immediate NAC recon-
struction through preservation of a skin island on
an advancement flap.23
Figure 6.11  •  Level II technique for a T3N0 cancer of the upper outer quadrant of the right breast. Preoperative
chemotherapy: partial response. Wide excision and mammaplasty. (a,b) Preoperative. (c) Resection weight 215 g.
(d) Result prior to contralateral symmetrisation.
a
b
c
d

Chapter 6
104
Technique
Modified inverted-T mammaplasty
Oncoplastic techniques for centrally located tu-
mours have recently been outlined by Huemer
et al.24 An inverted-T incision is preferred, similar
to that used in a superior pedicle mammaplasty. The
only modification is that the two vertical incisions
encompass the NAC, which is removed together
with the tumour. The breast shape is reconstructed
as already demonstrated for the superior pedicle ap-
proach. The NAC is usually reconstructed at a later
stage, after completion of radiotherapy, although it
can be reconstructed during the same procedure. A
modification of this technique is to leave a circular
island of skin or an inferior dermoglandular flap,
which is relocated in the position of the new NAC
and produces symmetry with the opposite NAC (see
Chapter 4).
Discussion
General
Until recently, the breast surgeon has been able to
provide only two options for patients with breast
cancer: either a modified radical mastectomy or
a wide local excision followed by radiation. BCS
indications have expanded, but only moderate
surgical advancements have been made since its
introduction.
The integration of plastic surgery techniques at the
time of tumour excision has delivered new alterna-
tives, enabling surgeons to perform major resections
involving more than 20% of breast volume without
causing breast deformity. This new combination of
oncological and reconstructive surgery is commonly
referred to as oncoplastic surgery. This has allowed
surgeons to extend the indications for BCS without
compromising oncological goals or aesthetic out-
comes. It is a logical extension of the quadrantec-
tomy technique described by Veronesi et  al.19 The
innovation of the quadrantectomy provided women
with a safe oncological option for conserving their
breasts.
A major advantage of OPS is avoiding the need
for secondary reconstruction by preventing major
breast deformities.28 Prior to the development of
OPS, patients with major deformities were referred
subsequently to plastic surgeons.29 A classification
system of these deformities has been described and
reconstructive techniques for breast deformity ­after
BCS have been developed30,31 (see Part  1 of this
chapter). Despite continued efforts to treat these
­deformities, the results of postoperative repair of
BCS defects in irradiated tissue are poor, regardless
of the surgical procedure or team.32,33 Immediate
­reshaping of the breast will eliminate some of the
need for these complex procedures.
Advances in OPS have been restricted by the
­diversity of techniques used, the lack of uniformity
in classifying oncoplastic techniques and the lim-
ited guidelines of the optimum OPS procedures in
the surgical literature. This has generated confusion
and difficulty in patient and technique selection. The
foundation of OPS starts with simple techniques that
are easily incorporated into everyday practice (level I
techniques), followed by acquiring the experience to
perform the various mammaplasty techniques utilised
for more extensive resections (level II techniques).
Indications for oncoplastic surgery
The main indication for OPS is the need to excise
large lesions or a significant percentage of the breast,
so permitting BCS for large lesions for which a
­standard excision with safe margins would be either
impossible or lead to major deformity. Extensive
ductal carcinoma in situ, invasive lobular carci-
noma, multifocality, and partial or poor responses
to neoadjuvant therapy are areas where there may
be benefits for OPS intervention. Standard BCS
with positive margins where re-excision is being
considered is an additional category of patients for
whom OPS is appropriate.34
Oncoplastic and oncological safety
Large randomised prospective clinical trials have
not validated the efficacy and safety of oncoplastic
The recurrence rates of quadrantectomy
compared favourably with those of lumpectomy, but
cosmetic outcomes were unpredictable and were
worse than a wide excision alone, so are no longer
advocated.25–27
With immediate reshaping employing OPS,
resections of larger cancers can now be achieved
with satisfactory cosmetic outcomes.

Oncoplastic procedures to allow breast conservation
105
techniques, but there is growing evidence, through
prospective series, that the techniques offer patients
safe and effective surgical treatment. Our prospec-
tive analysis of over 100 patients undergoing OPS
at our institution demonstrated 5-year overall and
disease-free survival rates of 95.7% and 82.8%,
respectively.11 Delay in adjuvant treatment was re-
lated to slow wound healing in only four patients,
but all patients were able to receive appropriate
postoperative radiotherapy and chemotherapy dur-
ing the study. The cosmetic results at a median of
49 months in our most recent series of 175 ­pateints
were favourable in 85% of patients.10 Final cos-
metic outcomes and complication rates are not
altered in patients undergoing neoadjuvant chemo-
therapy. A more recent retrospective review of 298
patients treated with OPS demonstrated a 5-year
recurrence-free rate of 93.7% and 94.6% overall
survival. This larger review confirms the equivalent
outcomes of OPS and standard BCS.35 Rietjens et al.
have reported long-term results from the European
Institute of Oncology indicating no local relapse in
the pT1 cohort. The pT2 and pT3 combined group
had a 5-year local recurrence rate of 8% and a mor-
tality rate of 15%. The overall local recurrence rate
was determined to be 3%.36
Integration into multidisciplinary
treatment
Clinical management is enhanced by OPS and does
not change the need for or adherence to the guide-
lines for preoperative chemotherapy. Our surgical
approach using OPS is fully integrated into the
multidisciplinary environment. Radiation treatment
is not disturbed by the extensive undermining dur-
ing OPS and has complication rates comparable
to BCS. There is no increase in treatment delays
with the more extensive level II techniques, and
the ­remodelling process does not affect continued
screening and radiographic follow-up of patients.37
Complications of oncoplastic
surgery
Mammaplasty techniques for cosmetic breast
­reduction have acceptable complication rates. Early
common complications include seroma, haema-
toma, infection, and skin or NAC necrosis leading
to delayed healing. Late complications during the
postoperative course may involve fat necrosis, loss
of nipple sensitivity and NAC necrosis.38,39
Extensive data are not available on complication
rates for oncoplastic procedures. Our prospective
evaluation of complications in an initial oncoplastic
surgery series demonstrated low seroma rates (1%),
but a higher overall incidence of delayed wound
healing (9%). A delay in postoperative treatment
was observed in only 4% of patients11 in our first
series, falling to 1.7% in our most recent publica-
tion.10 This complication rate is not dissmimilar to
that for cosmetic mammaplasty despite the need for
greater glandular undermining in OPS compared to
cosmetic breast reduction to achieve volume redis-
tribution to less favourable tumour locations.
Surgeons embarking on OPS should be aware of
complications, their frequency and the factors that
increase this risk. Glandular necrosis is the most
challenging complication. Patient selection and
careful surgical technique will avoid this.
Areas of fat necrosis can become infected and cause
wound dehiscence resulting in postoperative treat-
ment delay. Our rates of delayed wound ­healing have
been reduced considerably since we incorporated the
third key element of breast ­density into our decision-
making process. Our complication rate is now less
than 5%, with no delay in postoperative treatment
over the last 150 cases. If fat necrosis does occur, li-
posuction with lipofilling or lipomodelling can result
in rapid resolution and good long-term results.
Limitations of oncoplastic surgery
We have identified four different reasons that limit the
use of OPS: patient characteristics, tumour size, sur-
gical level of difficulty and increased operative time.
Patient considerations including breast size and
comorbidities are integrated into the initial evalua-
tion. Although level I procedures can be applied to
all patients, level II OPS is of limited value in women
with small breast size, either A or smaller B cups.
For these patients with small breasts who require
Aggressive undermining of the skin envelope
and gland from the pectoralis fascia can lead to
glandular necrosis if the breast is fatty, as such
breasts have less vascularity compared to glandular
breasts.

Chapter 6
106
excision of greater than 20% of the breast volume,
immediate lipofilling, a latissimus dorsi miniflap or
a total mastectomy with immediate reconstruction
should be considered. Immediate lipofilling works
best for excisions in areas where cosmetic outcomes
can be poor (upper inner quadrant, lower half of the
breast) in a patient with small breasts where the to-
tal volume of tissue excised is small but constitutes
a significant percentage of the total breast volume.
Comorbidities that increase the risk of tissue necro-
sis, such as history of smoking, diabetes and obesity,
must also be considered during surgical planning.
Once an acceptable risk is established for the ­patient,
then tumour characteristics are used to decide the ap-
propriate procedure and the best ­approach. Excision
of tumours too large to redistribute volume into
the index quadrant may require a volume replace-
ment procedure such as a latissimus dorsi miniflap.3
Location of the tumour is also critical, as upper inner
quadrant tumours have few volume redistribution
solutions, so immediate lipofilling in this location is
the current best option.
Difficulty in performing advanced level II tech-
niques comprises another category of limitation.
However, training for OPS can be acquired grad-
ually and level I techniques do not require any
­advanced training. Another solution for the more
complex cases is to incorporate a plastic surgeon in
the multidisciplinary team. This may be the best op-
tion for most breast surgeons that do not wish to
or do not have the time to invest in specific training
for complex level II techniques. The big advantage
of incorporating a plastic surgeon and an oncoplas-
tic surgeon is that it allows simultaneous bilateral
procedures, which reduce operating time. This can
be difficult to arrange logistically, so dual training of
breast surgeons is an alternative long-term solution.
Finally, can the additional time required for advanced
procedures be justified? The increased length of the
initial operation does translate into major benefits
for both the patient and the surgeon. OPS leads to an
overall reduction in operation time for many patients
because it is more likely to achieve free margins in one
procedure. The reduction in re-excision rates improves
resource management for the whole cohort of patients.
The greater amount of time utilised during the initial
procedure also has the added benefit of reducing de-
formity rates, thus eliminating the need for repair of
partial mastectomy defects. It also reduces the numbers
who require mastectomy and breast reconstruction.
Oncoplastic evolution and
revolution
As surgical practice guidelines continue to evolve
in the field of breast surgery, the training of future
breast surgeons should include OPS techniques and
rely on the experience and methodology gained
from the fields of both surgical oncology and plas-
tic and reconstructive surgery. Growth and accep-
tance of OPS as an alternative to BCS have seen an
­active collaboration between the divisions of breast
and plastic surgery in the UK and much of Western
Europe.
The pathway for obtaining the necessary training dif-
fers throughout the surgical world. In the UK, a formal
oncoplastic training programme has already been es-
tablished. Participants in this programme obtain both
plastic and reconstructive training, as well as experi-
ence in the surgical oncological management of breast
cancer. France has also witnessed the creation of a
formal certification programme for breast surgeons in-
terested in OPS. The programme involves clinical men-
toring, technical lectures and a standardised written
examination. The interest in OPS continues to expand,
with courses on offer at the major breast surgery con-
ferences in the USA and Europe. These courses provide
the necessary background to complete level I proce-
dures, but do not allow for application of level II OPS.
Conclusions
The proliferation of oncoplastic publications in the
surgical literature is a direct result of the awareness
of the advantages of OPS.
The ultimate goal is to allow large-volume resec-
tions with free margins and fewer mastectomies
than are currently obtainable with standard BCS.
OPS is best stratified into two levels. Three key
­factors have been defined – excision volume, tumour
location and glandular density – and these form the
basis of a cohesive set of surgical principles and teach-
ing guidelines. The goal for developing an OPS classifi-
cation and a quadrant-by-quadrant atlas is to improve
communication between surgeons and their patients.
Oncoplastic surgery allows large resections
of breast tissue with favourable cosmetic
outcomes and integrates easily into the standard
multidisciplinary approach for BCS.

Oncoplastic procedures to allow breast conservation
107
Key points
• Volume displacement is most suitable for patients with medium or large breasts who are willing to
undergo breast reduction (often bilateral), avoiding more major reconstructive surgery.
• Volume displacement allows large-volume resection of tissue without cosmetic penalty.
• Volume displacement can be designed around modifications of the superior pedicle, inferior
pedicle and round-block techniques.
• Immediate lipofilling performed at the same time as a wide local excision of the cancer is a new
technique currently being evaluated to improve cosmetic outcomes in patients with smaller breasts
where excision of even a small cancer would produce a poor cosmetic outcome.
• Specific training is required to be able to perform level II techniques but all surgeons doing breast
surgery should be able to perform level I oncoplastic surgical techniques.
• Training in breast surgery should include training in oncoplastic surgery.
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109
7
Anees B. Chagpar
Introduction
While there are aspects of breast surgical oncology
that have moved towards a more radical approach,
the management of the axilla has tended to become
incrementally less invasive. Although it is clear that
the status of the axillary lymph nodes continues to
be the most significant prognostic marker in the
management of breast cancer patients,1 removal of
lymph nodes carries no survival benefit.2,3 As such,
the purpose of axillary surgery in the context of
breast cancer management is primarily for staging
and local control.
The last several decades have witnessed a metamor-
phosis in terms of management of the axilla, with
significant paradigm shifts occurring within the last
several years. Historically, a complete axillary node
dissection with removal of level I and II lymph nodes
or even levels I–III was standard (Fig. 7.1), and while
this operation provided excellent prognostication
and local control, it was associated with significant
morbidity in terms of lymphoedema and decreased
range of movement of the shoulder. Through the pio-
neering efforts of Cabanas,4 who first coined the term
‘sentinel node’ based on cadaveric studies of penile
cancer, and the subsequent groundbreaking work of
Donald Morton, who introduced this into the man-
agement paradigm in melanoma,5 sentinel node bi-
opsy has revolutionised breast cancer treatment.
The concept of sentinel node biopsy is that one can
map the lymphatic drainage of a tumour to the first
draining lymph nodes, and that these nodes will be
representative of the lymphatic basin. David Krag and
Armando Giuliano6–8 introduced the technique into
clinical practice for breast cancer. While initially con-
sidered an investigational procedure, large validation
studies9–11 have confirmed that sentinel node biopsy
is a safe, reliable, minimally invasive procedure that
accurately stages the axilla. Subsequent randomised
controlled trials12 have corroborated these findings
(Table 7.1). The National Surgical Adjuvant Breast
and Bowel Project B-32 trial found overall survival,
disease-free survival and locoregional recurrence were
equivalent between patients who were randomised to
sentinel node biopsy followed by routine axillary dis-
section compared with sentinel node biopsy followed
by axillary node dissection only in sentinel node-pos-
itive patients.12 Given these trial data and those from
numerous other studies, sentinel node biopsy is now
considered the standard of care in the management of
patients with clinically node negative breast cancer.
Sentinel node biopsy has been validated
in large cohort studies,9–11 as well as randomised
controlled trials (like the NSABP B-32 trial),12
which demonstrated that the false-negative rate
is low, and that survival is no different for node-
negative patients who undergo sentinel node
biopsy compared with axillary node dissection.
Sentinel node biopsy is therefore a safe, accurate,
and minimally invasive technique to stage the
axilla in patients with breast cancer, and should be
considered the standard of care.
The axilla: current management including
sentinel node and lymphoedema

Chapter 7
110
Sentinel lymph node biopsy:
technique
Injection material/location
Considerable debate has surrounded the type of
injection material used for sentinel node mapping.
Some have advocated the use of blue dyes (such as
patent blue V or Isosulphan blue) (Fig.  7.2) alone
(severe ­hypersensitivity reactions with these drugs
occur in approximately 1 in every 2000 patients),
while others have preferred the use of radioactive
tracers (such as technetium-99-labelled sulphur colloid
or albumin). Still others have advocated the use of
agents together. Numerous retrospective studies have
found that while the false-negative rates are similar
for the three techniques,7,10,13–15 identification of
sentinel nodes is improved with the use of a com-
bined technique.16 A recent prospective trial found
that identification rates were 99.1% when dual trac-
ers were used, as opposed to 93.8–95.6% for blue
dye and 96.0–96.2% for radioactive tracer.17 An
approach that uses radioisotope in all patients and
adds blue dye only in those patients where radio-
isotope uptake into sentinel lymph nodes is not ap-
parent has appeal in that it reduces the number who
require blue dye.
While originally many practitioners injected tracers
at the site of the tumour, the concept of subareolar
injection is appealing, particularly for non-palpable
and/or multiple tumours, given the embryologic ori-
gins of the lymphatics in Sappey's plexus. A number
of authors have found that subareolar injection iden-
tifies the same sentinel node as a peritumoural tech-
nique,18,19 has a high identification rate, and the same
false-negative rate as other techniques.17,20 Therefore,
while the presence of multifocal/multicentric tumours
had once been thought to be a relative contraindica-
tion to the use of sentinel node biopsy, more recent
Level III nodes
Level I nodes
Level II nodes
Internal
mammary
nodes
Pectoralis minor
Axillary vein
Figure 7.1  •  Anatomy of the axillary nodes and levels
of axillary nodes related to the pectoralis minor. Level I
nodes below and lateral, level II nodes under muscle and
level III nodes medial to the muscle.
Study
Follow-up metric
ALND (95% CI)*
SLNB (95% CI)†
Zavagno et al.85
5-year DFS
5-year OS
89.9% (85.3–93.1%)
95.5% (92.2–97.5%)
87.6% (83.3–90.9%)
94.8% (91.6–96.8%)
Krag et al.12
8-year DFS
8-year OS
82.4% (80.5–84.4%)
91.8% (90.4–93.3%)
81.5% (79.6–83.4%)
90.3% (88.8–91.8%)
Veronesi et al.86
10-year DFS
10-year OS
88.8% (84.6–92.9%)
89.7% (85.5–93.8%)
89.9% (85.9–93.9%)
93.5% (90.3–96.8%)
Table 7.1  •  Prospective randomised controlled trials validating sentinel lymph node biopsy
ALND, axillary lymph node; DFS, disease-free survival; OS, overall survival; SLNB, sentinel lymph node biopsy.
*Sentinel node biopsy followed by routine axillary node dissection.
†Sentinel node biopsy followed by axillary node dissection only in sentinel node-positive patients.
Figure 7.2  •  Sentinel lymph node biopsy – blue-stained
lymphatic leading to blue node.

The axilla: current management
111
studies (many of which used a subareolar injection
technique, although some utilised multiple peritu-
moural injections) have found the accuracy, identifi-
cation and false-negative rates to be similar to smaller
unifocal cancers.21
Use of lymphoscintigraphy
Lymphoscintigraphy is often used in melanoma,
where drainage patterns can vary widely; however,
in breast cancer, where 98–99% of lymphatics
drain to the ipsilateral axilla, (Fig. 7.3) lymphos-
cintigraphy has not been found to be of significant
value (uptake of sentinel nodes of radioisotope
takes minutes only, allowing injection of isotope
after induction of anaesthesia).22,23 In cases of re-
current breast cancer, however, particularly if 10 or
more lymph nodes have previously been removed,
alternative drainage pathways may be encountered
and lymphoscintigraphy is recommended.24 Even
in patients who have had prior complete axillary
node dissections, Kaur et  al. have demonstrated
that lymphoscintigraphy can identify drainage in
29% of patients and, of these, drainage may be
non-axillary (contralateral and/or internal mam-
mary) in 38% of cases.25 Furthermore, of the
non-axillary sentinel nodes biopsied in the recur-
rent setting, 40% were positive and thus may alter
management plans.25
Intraoperative evaluation
Sentinel nodes may be sent for intraoperative patho-
logical evaluation so as to minimise the possibility of
the need for a subsequent completion axillary node
dissection in node-positive patients. A number of
techniques have been evaluated for intraoperative
evaluation – most commonly, frozen section and
touch imprint cytology.
Frozen section is the most common technique
used, and is associated with a specificity of 99–
100% and a sensitivity of 57–74%.26 The sensitiv-
ity is far better for macrometastases (84–92%) than
micrometastases (17–61%),26 and may be particu-
larly difficult to interpret in patients with invasive
­lobular carcinomas who have cytologically bland
cells and an infiltrative growth pattern. Nonetheless,
the overall accuracy of this technique is 83–91%.26
Tew et al. conducted a meta-analysis of 31 studies
of touch imprint cytology, and found that specific-
ity and sensitivity of this technique were 94–100%
and 34–95% respectively.27 Pooled estimates from
11 studies comparing macro- and micrometastases
found that the sensitivity for touch imprint cytology
was significantly better for the larger deposits: 81%
(95% confidence interval (CI) 74–86%) vs. 22%
(95% CI 14–33%) for macro- and micrometastases,
respectively.27 On a more global level, the sensitivity
of touch imprint cytology is lower than that of frozen
section (62% (95% CI 53–70%) vs. 76% (95% CI
65–84%)), while specificity is comparable for both
(99%).27 Molecular techniques are available that de-
tect cancer cells in sentinel nodes but these have not
found widespread utility.
While intraoperative evaluation has long been advo-
cated to avoid a second operative procedure, given that
the majority of screen-detected breast cancer patients
will be node negative, and that node-positive patients
may not always require axillary node dissection (see
Dual tracer technique is superior to use of blue
dye or radioactive tracer alone in terms of sentinel
node identification and false-negative rates, and is
the technique of choice to identify sentinel nodes.16,17
The subareolar injection technique has been found to
be accurate in finding sentinel nodes in the setting of
multifocal and multicentric breast cancer.17
Figure 7.3  •  Scintiscan showing drainage of
technetium-99 m human albumin colloid to show multiple
sentinel axillary nodes.
Lymphoscintigraphy is of limited utility in
routine sentinel node biopsy; however, it should be
considered in the setting of recurrent breast cancer,
where it may be able to demonstrate alternative
drainage pathways.

Chapter 7
112
‘Is axillary node dissection necessary in node-positive
patients?’ below), the value of intraoperative evalua-
tion of sentinel nodes is under scrutiny.
Sentinel lymph node biopsy:
controversial situations
While sentinel node biopsy is widely accepted as the
standard of care for lymph node evaluation for pa-
tients with early stage clinically node negative inva-
sive breast cancer, its use is less clear-cut in certain
controversial situations.
Prophylactic mastectomy
For women at high risk who are undergoing pro-
phylactic mastectomy, some have advocated sentinel
node biopsy, as this avoids the need for subsequent
axillary surgery if there is an occult breast cancer
that is noted on final pathology, and the sentinel
node is negative. Others, however, have argued
that the risk of there being a cancer with associated
lymph node metastasis is so low in the prophylac-
tic setting that routine sentinel node biopsy, despite
being of minimal additional morbidity, is not war-
ranted. In a meta-analysis of six papers including
1251 patients who underwent 1343 prophylactic
mastectomies, the rate of occult invasive cancer was
1.7% and the rate of positive sentinel nodes was
1.9%.28 Patients with positive sentinel nodes in the
prophylactic setting have often been found to have
had a locally advanced breast cancer in the origi-
nally treated breast so, in these patients, sentinel
node biopsy may be warranted when a prophylactic
contralateral mastectomy is being performed.28,29
Ductal carcinoma in situ (DCIS)
Some have argued that patients with DCIS who
are at high risk of having concomitant invasive dis-
ease should have a sentinel node biopsy at the time
of their excisional surgery to obviate the need to
­return to the operating room for a sentinel lymph
node biopsy should an invasive focus be found on
final pathology. The rate of DCIS on large core bi-
opsy being upgraded to invasive disease on final pa-
thology is reported to be up to 47%.21,30–32 Fewer
samples and the use of non-vacuum-assisted devices
increase the rates of underestimation of invasive dis-
ease.32 Further, clinical factors such as young age, a
palpable mass, large tumour size by imaging, high
grade, and comedo necrosis are also associated with
an increased risk of concomitant invasive disease in
patients with core biopsy diagnosis of DCIS.33,34
While some argue that such patients should have
a sentinel lymph node biopsy, others prefer to con-
firm diagnosis of invasive disease before subjecting
patients to a potentially unnecessary lymph node
evaluation procedure. While sentinel node biopsy is
minimally invasive and associated with few risks,
it is not innocuous. It is well established that sen-
tinel node biopsy can be performed after breast-
conserving surgery has been performed. A recent
meta-analysis comparing sentinel node identifica-
tion and false-negative rates for patients who un-
derwent surgical versus needle biopsy found that
rates were comparable (sentinel node identification
rates 91.3% vs. 92.8%; false-negative rates 12.3%
vs. 9.9%).35 Therefore, prior surgery does not af-
fect the ability to perform this technique accurately
and consensus guidelines have accepted that senti-
nel node biopsy should not be performed routinely
in patients with DCIS undergoing breast-conserving
surgery. It is accepted that for patients undergoing
mastectomy for DCIS, a sentinel lymph node biopsy
should be considered at the same time as the mas-
tectomy,36,37 as this technique cannot be performed
once the breast is removed and an invasive focus is
identified. In those with confirmed DCIS the node
positivity rate is low at <1%.
Neoadjuvant chemotherapy
Many patients with locally advanced or inflamma-
tory breast cancers undergo neoadjuvant systemic
therapy, and the use of preoperative chemotherapy is
becoming increasingly popular even in patients with
operable breast cancer, as a means to increase breast
conservation rates as well as to evaluate in  vivo
Routine use of sentinel node biopsy in patients
undergoing prophylactic mastectomy is not
recommended, given that the finding of lymph
node metastases in this setting is low. The risk of a
positive sentinel node in the setting of contralateral
prophylactic mastectomy is increased in patients who
have had a mastectomy in the opposite breast for
locally advanced breast cancer. Therefore, in such
patients sentinel node biopsy should be considered.
Sentinel node biopsy should be considered
for patients undergoing mastectomy for
DCIS.36,37

The axilla: current management
113
tumour response to therapy. The burgeoning wide-
spread use of neoadjuvant ­chemotherapy has led to a
plethora of controversies regarding the accuracy and
timing of sentinel node biopsy in this situation.
Some have argued that sentinel node biopsy should
be performed prior to neoadjuvant systemic therapy.
Studies have demonstrated a high identification
(98–100%) and an exceedingly low false-negative
rate (0%) in this situation.38 Given that this technique
is performed prior to any therapy, there can be no
confounding of negative results as a result of therapy,
which has resulted in false-negative rates as high as
39% in selected series39 reported in patients who
have a sentinel node biopsy following chemotherapy.
Others, however, have argued that to do a sentinel
node biopsy prior to chemotherapy eliminates the op-
portunity to spare the 2–35% of patients who have
a pathologically complete response in the axilla the
morbidity of an axillary dissection.38 Furthermore,
to evaluate sentinel nodes after neoadjuvant therapy,
when surgery for the primary tumour is planned, may
reduce the need for a second operative procedure.
A recent meta-analysis has demonstrated that sen-
tinel node biopsy after neoadjuvant chemotherapy is
associated with identification rates of between 71%
and 100% (summary estimate 90.9%), false-negative
rates between 0% and 39% (summary estimate
10.5%), and accuracy rates between 77% and 100%
(summary estimate 94.4%).40 Two groups have per-
formed trials of sentinel lymph node biopsy (SLNB)
in the neoadjuvant setting in women with node posi-
tive breast cancer whose nodes are cleared by chemo-
therapy. The issue these trials addressed is whether
axillary dissection (AD) can be avoided in respond-
ing patients. The ACOSOG Z1071 trial was a single
arm study of 756 women (T0-4, N1-2, M0) undergo-
ing neoadjuvant chemotherapy (NAC) with axillary
nodal involvement confirmed by ultrasound guided
FNA or core biopsy.41 Some patients had the involved
nodes clipped. Following completion of NAC, SLNB
was performed and there had to be at least 2 SLNs
removed before proceeding to AD. The primary end-
point was to determine if the false negative rate (FNR)
was <10% in women with N1 disease who had at least
2 sentinel nodes biopsied after NAC. Of 643 patients
with a SN identified, 40.3% had a complete patho-
logical response in the axilla. SLNB correctly identi-
fied nodal status after NAC in 84% of 695 patients.
There was a 12.6% false negative rate (higher than
the primary endpoint of 10%). The false negative rate
(FNR) was significantly lower (10.8%) if dual tracer
with both radiolabelled colloid and blue dye was used,
compared with blue dye (4/24 - 16.7%) or radioiso-
tope alone (20/101 - 20%) (p=0.046). The FNR was
lower if more than 2 nodes were examined, 9.8% for
3 sentinel nodes, 6.7% for 4 sentinel nodes, but 11%
for 5 or more, p=0.004 for trend. Placement of a clip
in the positive node at diagnosis also decreased the
FNR to 7.4% vs 13.6% without clip placement. An
apparent chemotherapy effect in the SNs removed as
marked by greater fibrosis or other histopathological
changes in the sentinel nodes was also associated with
a lower FNR (10.8% vs 13.5% without). Avoiding a
high rate of false negatives in patients with node posi-
tive disease is essential and the results of this study
highlight that technical factors are important for accu-
rate SLNB after NAC. Performance can be improved
by the use of dual tracer, examination of a minimum
of 2 sentinel lymph nodes and placement of clips in in-
volved nodes at diagnosis. These are the requirements
if this technique is to be used after NAC.
The German Breast Group addressed the issue of op-
timal timing for sentinel lymph node in the prospec-
tive German, multi-institutional SENTINA-trial.42 Of
1737 patients entered, 1022 women were clinically
node negative and underwent SLNB prior to NAC.
The SLN detection rate in this group of women was
99.1 % (1013/1022). Among these, 360 patients had
histologically involved nodes and these women under-
went a second SLNB followed by AD after NAC. The
SLN detection rate in these patients undergoing their
second SLNB after NAC was 60.8% (219/360). 592
patients, who presented initially with suspicious axil-
lary nodes converted to a cN0 status after NAC and
underwent SLNB, combined with AD. The SLN detec-
tion rate in these women was 80.1% (474/592). The
difference between the detection rates of these three
groups was highly statistically significant (p < 0.001).
The false negative rate in patients who had a repeat
SLNB after NAC was very high at 51.6% and so per-
forming 2 SLNB before and after NAC cannot be
recommended. In patients who were down-staged with
NAC from positive to negative axillary status, the false
negative rate was 14.2%. There are many aspects of the
SENTINA study which are unclear. There was no use of
clips in nodes. Many sentinel nodes were visualised on
scans but not removed. No information has so far been
presented on false negative rates related to the number
of nodes removed. The results from these two studies are
not that different. SLNB after NAC is a difficult proce-
dure. While SLNB before NAC is accurate, patients with
involved nodes at diagnosis require AD but many will

Chapter 7
114
have their nodes cleared by NAC. For this reason SLNB
after chemotherapy has started to be incorporated into
clinical practice in selected N1 patients whose primary
cancer and nodes respond to NAC. It can however only
be recommended when strict criteria are adhered to.
Isolated tumour cells and
micrometastases
More thorough pathological evaluation of sen-
tinel lymph nodes using serial sectioning and
immunohistochemistry has allowed identification of
occult ­metastases in up to 31% of previously ‘node-
negative’ patients.43 This stage migration, and the rel-
evance of this previously undetected disease, has been
a source of considerable controversy. The American
Joint Committee on Cancer classifies sentinel node
metastases into three categories: ‘isolated tumour cells’
for metastases <0.2 mm (which are considered node
negative, pN0(i+); Fig. 7.4); ‘micrometastases’ for de-
posits between 0.2 and 2.0 mm (considered node posi-
tive, pN1mi; Fig. 7.5); and ‘macrometastases’, defined
as deposits >2.0 mm (also considered node positive,
pN1a; Fig.  7.6).1 These somewhat arbitrary cut-offs
have generated debate as to the true implications of
both isolated tumour cells and micrometastases.
In a pooled analysis of 58 studies of patients with me-
tastases <2 mm, de Boer et al. found that the presence
of this small-volume disease in the axillary lymph node
was associated with a reduction in survival, which was
independent of other prognostic variables (hazard ra-
tio (HR) = 1.44; 95% CI 1.29–1.62).44 Data from the
National Surgical Adjuvant Breast and Bowel Project
(NSABP) B-32 trial (Fig. 7.7) showed that any occult
metastases were associated with a small increased
risk of death (HR = 1.40; 95% CI 1.05–1.86), any
outcome event (HR = 1.31; 95% CI 1.07–1.60) and
distant disease (HR = 1.30; 95% CI 1.02–1.66).45 On
subgroup analysis, isolated tumour cells had a smaller
increased risk of death, any outcome event and distant
disease than micrometastases. The hazard ratios (95%
CI) for these three outcomes were 1.27 (1.04–1.54),
1.18 (1.02–1.33) and 1.19 (1.00–1.41), respectively,
for isolated tumour cells, and 1.60 (1.32–1.96), 1.38
(1.15–1.60) and 1.41 (1.19–1.68), respectively, for mi-
crometastases.45 The absolute differences in outcomes
were, however, very small and the recommendations
of the trial committee were that the differences were
such that a search for occult metastases by immu-
nohistochemistry on a routine basis when assessing
sentinel lymph nodes could not be supported. The
‘Micrometastases and Isolated Tumour Cells: Relevant
and Robust, Or Rubbish’ (MIRROR) Study also found
that patients with both isolated tumour cells and those
with micrometastases who did not receive systemic ad-
juvant therapy had a higher adjusted event rate than
node-negative patients (HR = 1.50, 95% CI 1.15–1.94
and HR = 1.56, 95% CI 1.15–2.13, respectively).46
A number of authors have evaluated the significance
of isolated tumour cells and micrometastases in terms
of the likelihood of there being other non-sentinel node
metastases (Table 7.2). Cserni et al., in a meta-analy-
sis of 25 studies, reported that up to 57% of patients
with isolated tumour cells or micrometastases had
non-sentinel node involvement.47 The pooled estimates
for non-sentinel node involvement vary with tumour
burden in the sentinel nodes, and are 20.2% (95% CI
Figure 7.4  •  Isolated tumour cells in an axillary
lymph node.
Figure 7.5  •  Micrometastases in an axillary lymph node.

The axilla: current management
115
15.5–24.9%) for micrometastases and 9.4% (95% CI
6.2–12.6%) for isolated tumour cells.47 In keeping with
these data, van Deurzen et al. found that 12.3% (95%
CI 9.5–15.7%) of patients with isolated tumour cells or
micrometastases had non-sentinel node involvement.48
Non-sentinel node
metastases
Prediction models
Given that a significant proportion of patients with a
positive sentinel node will have no further disease in their
non-sentinel lymph nodes, a number of authors have
Figure 7.6  •  Axillary lymph node with an obvious macrometastasis: (left) low power; (right) high power.
a
b

Study

N

Type of deposit
Non-SLN
metastases
Nos et al.87
123
140
ITC/micrometastases
Macrometastases
8 (6.5%)
55 (39.3%)
Viale et al.88
116
318
794
ITC
Micrometastases
Macrometastases
17 (15.8%)
68 (21.3%)
399 (50.3%)
Houvenaeghel et al.89
187
301
ITC
Micrometastases
30 (16.0%)
43 (14.3%)
Gipponi et al.90
116
Micrometastases
16 (13.8%)
van Deurzen et al.91
23
101
193
ITC
Micrometastases
Macrometastases
3 (13.0%)
20 (19.8%)
93 (48.2%)
Chen et al.56
3
28
128
ITC
Micrometastases
Macrometastases
1 (33.3%)
6 (21.4%)
74 (57.8%)
Table 7.2  •  Non-sentinel node metastases in patients with isolated tumour cells and micrometastases
SLN, sentinel lymph node.
Percentage alive
0
20
40
60
80
100
0
2
4
6
8
Years of follow-up
Years of HR = 1.3 P = 0.03
5 yr Overall Survival: 94.60/0 v 95.8%
No occult metastases
Occult metastases
Figure 7.7  •  Data from NSABP B32 trial comparing
overall survival in patients with no metastases vs occult
metastases demonstrated on immunohistochemistry.

Chapter 7
116
developed nomograms and clinical prediction models in
an effort to spare some patients with involved sentinel
nodes the morbidity of axillary node dissection. Perhaps
the best known of these is the Memorial Sloan-Kettering
Nomogram developed by Kim van Zee and colleagues.
This model predicts the probability of non-sentinel node
status based on a number of factors, including patholog-
ical tumour size, grade, lymphovascular invasion, multi-
focality, oestrogen receptor status, the number of positive
and negative sentinel lymph nodes, and the method used
to identify sentinel lymph node metastases (either by im-
munohistochemistry, routine haematoxylin–eosin stain-
ing, serial sectioning with haematoxylin–eosin, or frozen
section).49 A number of other models have also been cre-
ated, including the Cambridge nomogram,50 the Mayo
nomogram,51 the Tenon model,52 the MD Anderson
score53 and the Stanford nomogram.54 All of these in-
clude some elements that are often available only after
the sentinel nodes have been examined histologically,
such as lymphovascular invasion and/or size of sentinel
node metastases. These elements are clearly important
in predicting non-sentinel node metastases, but in order
to assist intraoperative decision-making, the Louisville
clinical prediction model was developed as a simple
clinical prediction model using variables that are avail-
able either pre- or intraoperatively, such as tumour size
category, number of positive sentinel nodes and number
of sentinel nodes removed.55
A recent study by Chen et al. evaluated all of these
models in a small independent cohort of 81 patients.56
All models were similar, with areas under the curve
ranging from 0.54 (95% CI 0.45–0.63) for the Stanford
model to 0.73 (95% CI 0.65–0.81) for the Cambridge.
Aside from these two outliers, all other models had ar-
eas under the curve ranging from 60% to 68%. The
false-negative rate for the prediction models ranged
from 0% in the Louisville model to 19.8% in the Tenon
model. There is a trade-off, however, between the false-
negative rate and the number of patients who fall be-
low the threshold for avoiding axillary dissection – so
that models such as the Louisville model that had a very
low false-negative rate often were more stringent and
allowed fewer patients to avoid an axillary dissection.
Is axillary node dissection
necessary in node-positive
patients?
While nomograms and models can help to define a
cohort of node-positive patients who are at low risk
of having non-sentinel node disease, the results of
recent randomised controlled trials appear to have
rendered such models irrelevant. The American
College of Surgeons Oncology Group (ACOSOG)
Z-0011 trial randomised 891 sentinel node-positive
patients to complete axillary node dissection versus
no axillary node dissection.57 All patients received
whole-breast tangential irradiation, which will have
covered some of the lower two-thirds of the axilla,
although no defined characteristics of the axillary
radiation dose were specified in the trial and radia-
tion fields used have yet to be reported. The median
total number of nodes removed was 17 in the axil-
lary lymph node dissection and two in the sentinel
lymph node biopsy group alone. The median num-
ber of nodes with histologically demonstrated in-
volvement was one in both groups; however, 27.3%
of patients having a subsequent axillary dissection
arm had non-sentinel node metastases.
With a median follow-up of 6.3 years, there was
no significant difference in axillary recurrence be-
tween the patients who had a complete axillary node
dissection (0.5%) and those who did not (0.9%).
The adjusted hazard ratio for locoregional recur-
rence comparing complete dissection with sentinel
node biopsy alone was 0.825 (95% CI 0.263–2.586,
P = 0.7411).55 Rates of locoregional recurrence did
not differ between the two arms; local recurrence-
free survival at 5 years was 96.7% (95% CI 94.7–
98.6%) in the sentinel lymph node biopsy alone
group, and 95.7% (95% CI 93.6–97.9%) in the axil-
lary lymph node dissection group (P = 0.28). Disease-
free survival did not differ significantly between the
two treatment arms; the 5-year disease-free survival
was 83.9% (95% CI 80.2–87.9%) for the sentinel
lymph node biopsy alone group and 82.8% (95% CI
78.3–86.3%) for the axillary lymph node dissection
group (Fig. 7.8). At a median follow-up of 6.3 years,
there was no evidence that sentinel lymph node bi-
opsy compared with axillary lymph node dissection
resulted in a statistically significant inferior survival
(Fig. 7.8). The unadjusted hazard ratio between the
two groups was in favour of sentinel lymph node
biopsy with a hazard ratio of 0.79 (90% CI 0.56–
1.10). The hazard ratio for overall survival, adjust-
ing for adjuvant therapy and age, was 0.87 (90% CI
0.63–1.23). The rates of wound infections, axillary
seromas and paraesthesia were significantly higher
for the axillary lymph node dissection group (70%
vs. 25%, P < 0.001). Lymphoedema was also sig-
nificantly more ­common in the axillary lymph node

The axilla: current management
117
dissection group (P<0.001), in accordance with
other comparisons of sentinel lymph node biopsy
and axillary lymph node clearance.
For many surgeons, this trial has been practice chang-
ing and has questioned the need for routine axillary
dissection in the setting of a positive sentinel node. It
should be noted, however, that this study had several
important exclusion criteria. Patients who had locally
advanced disease or who underwent neoadjuvant che-
motherapy were not candidates for the trial. Further,
only patients with fewer than three positive nodes
were eligible. Patients must have had breast-conserv-
ing surgery with whole-breast irradiation (acceler-
ated partial breast irradiation or brachytherapy was
an exclusion factor), and most had systemic adjuvant
therapy. There are also some other concerns about the
trial, specifically the amount of missing data, the inclu-
sion of a number of ineligible patients, the selective na-
ture of the patients entered into the study and the large
numbers lost to follow-up. Despite the numbers lost
to follow-up, data were complete on survival so the
primary end-point does appear secure. Furthermore,
although the statistical end-point was achieved, it may
be underpowered to show a small but potentially clini-
cally significant effect on outcome. There are, how-
ever, large amounts of reassuring data on patients who
have involved nodes treated by sentinel node biopsy
alone, so the results of the Z-0011 study do not stand
alone in indicating that it should no longer be routine
practice to advise complete axillary dissection on all
patients with a positive sentinel node.
The International Breast Cancer Study Group
(IBCSG) 23-01 recently reported as yet unpublished
results at the San Antonio Breast Cancer Symposium
in December 2011. In this trial, 934 patients with
sentinel nodes involved with micrometastases were
randomised to complete axillary node dissection com-
pared with no complete axillary node dissection.58
Unlike the ACOSOG Z-0011 trial, only 75% of pa-
tients had breast-conserving surgery; 89% of patients
in the group randomised to axillary node dissection
received adjuvant breast or chest wall radiation ther-
apy, and 92% of patients randomised to no com-
plete axillary dissection received radiation. Five-year
Figure 7.8  •  Disease-free and overall survival from the Z-0011 study.
Log-rank P = .14
Survival (%)
0
10
20
30
40
50
60
70
80
90
100
0
1
2
3
4
5
6
7
8
Years
Alive and disease-free
420
369
335
310
286
226
152
83
37
436
395
363
337
307
231
147
81
36
Survival (%)
0
10
20
30
40
50
60
70
80
90
100
0
1
2
3
4
5
6
7
8
Years
Alive
Log-rank P = .25
Number of patients at risk
ALND

420
408
398
391
378
313
223
141
74
SLND alone
436
421
411
403
387
326
226
142
74
ALND
SLND alone
a
0.5
1.0
1.3
2.0
Hazard Ratio (90% CI)
for overall survival
Favours
SLND Alone
Unadjusted
Favours
ALND
Adjusted
b

Chapter 7
118
disease-free survival was 87.3% for the 464 patients
who underwent axillary node dissection and 88.4%
for the 467 patients who did not undergo this pro-
cedure, with low rates of axillary recurrence in both
groups. Locoregional recurrences were seen in five
patients (1.1%) of those having no axillary dissec-
tion: two in the axilla alone, one in the axilla together
with internal mammary nodes, one in the breast and
axilla, and one in the internal mammary nodes alone.
There was only one patient in the axillary dissection
group (0.2%) who developed locoregional recurrence
and this was an isolated axillary recurrence. Overall
survival was 98% at 5 years in both groups.
The European Organisation of Research and
Treatment of Cancer (EORTC) 10981 ‘After
Mapping of the Axilla, Radiotherapy or Surgery?’
(AMAROS) trial aims to assess whether surgery or
radiation to the axilla produce similar outcomes in
sentinel node-positive patients. Between 2001 and
2005, 2000 sentinel node-positive patients were
enrolled in the trial, and were randomised to either
complete axillary node dissection or axillary radio-
therapy, and the trial continues.59 Long-term recur-
rence and survival data are as yet unpublished, but
this trial should provide valuable information re-
garding the relative utility of dedicated axillary radia-
tion and axillary dissection in providing locoregional
control as well as the relative rates of lymphoedema.
Complications of axillary
surgery
Much of the significant effort that has gone into
predicting non-sentinel node metastases and trials
has been aimed at avoiding axillary dissection in the
setting of a positive sentinel node and thus avoiding
the complications associated with axillary surgery.
While even sentinel node biopsy is not innocuous,
because of the risk of anaphylaxis associated with
blue dye,60 the risks of numbness, lymphoedema
and decreased range of motion are significantly
less with sentinel node compared with full axillary
dissection.61–63 The ‘Axillary Lymphatic Mapping
Against Nodal Axillary Clearance’ (ALMANAC)
trial demonstrated, in a multicentre randomised
controlled trial, that patient-reported quality of life
and arm function were ­significantly better with sen-
tinel node biopsy than ­axillary node dissection.64
In addition, using both subjective and objective
criteria, they found that sentinel node biopsy was
associated with less lymphoedema (relative risk
(RR) = 0.37; 95% CI 0.23–0.60; 5% vs. 13%) and
numbness (RR = 0.37; 95% CI 0.25–0.5; 11% vs.
31%) at 1 year than axillary dissection.64
Lymphoedema is one of the most dreaded complica-
tions of axillary surgery and/or radiation therapy. The
rate of lymphoedema varies in part by the definition
that is used, and can range from subclinical ­swelling
that is detected by bioimpedence monitoring or
perometer measurements to massive elephantiasis of
the upper extremity. In general, however, up to 20%
of patients may have some degree of lymphoedema
after axillary node dissection. In a meta-analysis of
22 studies, axillary node dissection had a relative risk
of 3.07 (95% CI 2.20–4.29) of developing lymph-
oedema compared to sentinel node biopsy alone.65
Axillary radiation therapy was also associated with a
relative risk of 2.97 (95% CI 2.06–4.28) of developing
lymphoedema compared to no axillary radiation.65
Given the longevity of breast cancer survivors, the
impact of axillary surgery on morbidity and quality of
life long term is important. Even in patients undergoing
a sentinel node biopsy alone, Liu et al., in a systematic
review, demonstrated a prevalence of late morbidity
that included pain (7.5–36%), decreased range of mo-
tion (0–31%), oedema (0–14%), weakness (11–19%)
and sensory disorders (1–66%).66 These effects de-
creased over time, and were more prevalent in young
women.66 Similar findings were noted in the NSABP
B-32 trial, which found that while arm morbidity was
less in the sentinel node biopsy group (as opposed to
those who underwent axillary node dissection), less
than 15% of patients in either group reported sig-
nificant symptoms or limitations beyond 12 months.67
Other prospective trials evaluating the morbidity of
sentinel node biopsy compared with axillary node dis-
section have reported similar findings (Table 7.3).
While sentinel node biopsy does cause morbidity,
this is significantly less than for complete axillary node
dissection.64,67 Quality of life, as well as functional
outcomes, are significantly better after sentinel node
biopsy alone than after axillary dissection.64,67
Axillary node dissection is not associated with
improved survival in sentinel node-positive patients,
and locoregional recurrence is low for patients
receiving whole-breast irradiation and systemic
therapy in patients with fewer than three positive
sentinel nodes.57 Consideration may be given to
omitting axillary node dissection in such patients.

The axilla: current management
119
Some have attempted to reduce morbidity follow-
ing sentinel node biopsy by adopting a technique in
which the lymphatics of the arm are also mapped,
and the nodes draining the upper extremity are
avoided.68,69 Some have argued that this ‘axillary re-
verse mapping’ or ARM technique does not reliably
identify arm lymph nodes, and that the ARM nodes
may harbour metastases or be the same nodes as
those draining the breast in a minority of patients.70
As yet, the true reduction in lymphoedema rates
associated with this technique remains to be deter-
mined, and this procedure remains investigational.
Imaging techniques
A number of authors have investigated various im-
aging modalities as an alternative or adjunct to sur-
gical staging of the axilla. The most well established
of these is ultrasound, which is often combined with
fine-needle aspiration for suspicious lymph nodes
(Fig. 7.8); however, other techniques such as posi-
tron emission tomography and magnetic resonance
imaging have also been described.
Ultrasound and fine-needle
aspiration
Axillary ultrasound and fine-needle aspiration
or core biopsy has been embraced as a means of
staging the axilla to avoid sentinel node biopsy
in node-positive patients, allowing them to pro-
ceed directly to axillary node dissection (Fig. 7.9).
Given the findings from the Z-0011 trial, the
value of this approach has been ­questioned as
not all node-positive patients may need axillary
dissection. Sentinel node biopsy in such patients
may still be valuable to determine whether less
than three sentinel nodes are involved. A number
of studies have found the sensitivity of ultrasound
with fine-needle aspiration to range from 21% to
86%, with higher rates being found in patients
with more extensive lymph node involvement.71
A recent meta-analysis found the sensitivity and
specificity of ultrasound in the detection of lymph
node metastases to be 79.6% (95% CI 74.1–84.2)
and 98.3% (95% CI 97.2–99.0), respectively.72
Furthermore, the rate of ultrasound-guided needle
biopsy yielding an insufficient sample was 4.1%
(interquartile range 0–10.9%).72 The role of ul-
trasound and fine-needle aspiration may therefore
need to be redefined. While some may argue that
patients who have a positive ultrasound-guided
fine-needle aspiration should proceed directly to
axillary node dissection given the propensity for
extensive disease in this population, others have
Figure 7.9  •  Ultrasound images of involved axillary
nodes in patients with breast cancer. All such nodes
should have fine-needle aspiration or core to confirm
whether the abnormal node is involved.

OR (95% CI) for SLNB vs. ALND

Lymphoedema
Decreased range of
motion

Numbness
Zavagno et al.85
0.48 (0.3–0.8)
0.55 (0.3–0.9)
0.51 (0.4–0.7)
Purushotham et al.92
0.30 (0.18–0.68)

0.32 (0.19–0.51)
Ashikaga et al.93
0.52 (0.43–0.65)
0.64 (0.53–0.79)
0.19 (0.15–0.23)
Mansel et al.64
0.37 (0.23–0.60)

0.37 (0.27–0.50)
Lucci et al.94
0.52 (0.26–1.06)

0.15 (0.06–0.37)
Table 7.3  •  Morbidity of sentinel node biopsy vs. axillary node dissection in prospective trials
ALND, axillary lymph node; OR, odds ratio; SLNB, sentinel lymph node biopsy.

Chapter 7
120
suggested that patients with limited nodal disease
identified in this manner could be treated with
sentinel node biopsy. This would give the option
of avoiding axillary dissection in some, given the
lack of survival benefit of removing lymph nodes,
and the widespread use of adjuvant therapy, which
may not change even as the number of positive
nodes involved increases.
Positron emission tomography
(PET)
PET has been explored as a potential means of
detecting disease in the axilla, but to date results
have been disappointing. In a meta-analysis of 26
studies, Cooper et al. found the sensitivity of PET
to be 63% (range 20–100%; 95% CI 52–74%),
with a specificity of 94% (range 75–100%; 95%
CI 91–96%). The sensitivity was somewhat im-
proved in studies evaluating PET-only (versus
PET–computed tomography (CT); 66% vs. 56%,
respectively); specificity, however, was improved
by PET-CT (versus PET-only; 96% vs. 93%, re-
spectively).73 Sensitivity was 11% for microme-
tastases (based on five studies of 63 patients) and
57% for macrometastases (based on four studies
of 111 patients).73
Magnetic resonance imaging (MRI)
MRI has become popular as a breast imaging tech-
nique and its utility in evaluating axillary lymph
nodes has also been investigated. In a meta-analysis
of nine studies, Harnan et al. found that the ranges
of sensitivity and specificity of this technique were
65–100% and 54–100%, respectively.74 Pooled
estimates for sensitivity and specificity were 90%
for each, but these varied significantly by tech-
nique. Ultra-small superparamagnetic iron oxide-
enhanced MRI had the highest sensitivity and
specificity (98% and 96%, respectively), gadolin-
ium-enhanced MRI performed less well (with a
sensitivity and specificity of 88% and 73%, respec-
tively) and magnetic resonance spectroscopy (based
on only one study) had sensitivity and specificity
of 65% and 100%, respectively.73 At the moment,
imaging (whether by ultrasound, PET or MRI) has
limited utility without histological confirmation of
lymph node metastases.
Management of
lymphoedema (see Box 7.1)
Given the need for histological confirmation of lymph
node metastases, surgical evaluation of axillary nodes
remains a major component of staging for patients
with breast cancer. Such surgical excision of nodes,
the vast majority of which are normal, carries with
it the risk of lymphoedema (Fig.  7.10), albeit in a
There are four cornerstones of treatment:
• Skin care is required to maintain good skin condition
and reduce the risk of infection.
• Exercise promotes lymph flow and maintains good
limb function.
• Manual lymphatic drainage is a gentle skin
massage that encourages lymph flow and is carried
out by a trained therapist.
• Support/compression with multilayer lymphoedema
bandaging is applied to reduce the size and improve the
condition of the limb to allow fitting of elastic compression
garments, which when fitted correctly control swelling and
encourage lymph flow. Compression garments should be
worn while the patient is exercising to reduce lymphatic
filtration. Maintaining an adequate weight helps to prevent
lymphoedema development, so dietary advice is important
in all patients, but particularly in those who are overweight.
Box 7.1  •  Management of lymphoedema
Figure 7.10  •  Lymphoedema of the left arm and hand.

The axilla: current management
121
relatively small proportion of patients. When it does
occur, however, there are several techniques for man-
agement of this upper extremity swelling.
Complete decongestive therapy
Often considered the primary modality for manag-
ing lymphoedema, complete decongestive therapy
consists of manual lymph drainage, compression gar-
ments/bandaging, lymphatic/decongestive exercises
and self-care education.75 Intermittent pneumatic
compression is often used as an adjunct to manual
drainage.76
Pharmaceutical interventions
While pharmaceutical interventions with diuretics,
benzopyrones and flavonoid derivatives have been
investigated as potential therapies in the setting of
lymphoedema, none have been found to be univer-
sally efficacious, and these modalities have been
largely abandoned.77
Surgical therapies for
lymphoedema
Historic operations, described by Sistrunk78 and
Thompson,79 aimed to create a connection be-
tween the superficial and deep lymphatic collec-
tion systems by resecting subcutaneous soft tissue
and deep fascia. While these procedures may
have reduced the size of lymphoedematous ex-
tremities, they also caused extensive scarring and
morbidity without any objective evidence that
new lymphatic pathways were created. Hence,
these procedures have been abandoned and are of
historic interest only. Liposuction has also been
proposed as a technique that could reduce the
volume of lymphoedematous extremities;80 how-
ever, given the risk of injury to residual lymphat-
ics, this technique may actually exacerbate this
condition. It is effective in arms with non-pitting
swelling with significant excess of fat in the sub-
cutaneous tissue.
Other procedures, aimed at draining excess
lymphatic fluid into other lymphatic or venous
vessels, have also been described. In particular,
some have advocated placing greater omental
flaps into the upper extremity while maintaining
continuity with the ipsilateral gastroepiploic ves-
sels through a subcutaneous tunnel in the chest.81
The concept behind this procedure is that the
omentum has more lymphatic vessels and that
excess lymph fluid may be drained through the
omental graft, although there is no objective
evidence for this. Some have had success with
lymphaticolymphatic bypass using lymphatic
vessels of the medial thigh as a free composite
graft to bypass routes between the upper arm
and the supraclavicular region.82 Others have
similarly found significant prolonged improve-
ment in lymphoedema using a lymphaticovenular
bypass;83 however, these procedures are still an-
ecdotal and not widely adopted.
Finally, microvascular lymph node transfer in
which inguinal lymph nodes are transplanted into
the axilla as part of a composite soft tissue graft
has been suggested.84 Although the hypothesis is
that this procedure would sprout new lymphatics
that would allow improved lymphatic drainage,
there are no data to demonstrate that lymphat-
ics regenerate from these nodes. Therefore, sur-
gical management of lymphoedema remains
investigational.
Conclusion
The management of the axilla has changed signifi-
cantly in recent  years. While lymph node status
remains one of the most important prognostic fac-
tors in breast cancer patients, routine axillary node
dissection should no longer be performed. Sentinel
node biopsy has been validated as a simple, ac-
curate and minimally invasive technique to stage
the axilla. While this had often been followed by
­routine dissection in the setting of node-positive
disease, recent trials have questioned the need for
this practice in all patients, given the increased
morbidity of complete dissection and the lack of
survival benefit in removing additional nodes.
There remain numerous controversies surround-
ing appropriate management of the axilla in breast
cancer patients, and this continues to be a fertile
area for further research.
Complete decongestive therapy remains the
initial treatment of choice for lymphoedema.
Pharmacological and surgical therapies are
investigational.

Chapter 7
122
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2007;25(24):3657–63.

127
8
D. Gareth R. Evans
Ava Kwong
Andrew D. Baildam
The genetics of breast cancer, risk-reducing
surgery and prevention
Introduction
The last 20 years have seen a substantial rise in our
knowledge of inherited breast cancer. It is now pos-
sible to identify women at very high levels of risk
of the disease. Whilst there are promising signs for
reducing breast cancer risk using hormonal and
other manipulations, the level of risk reduction still
falls far short of that provided by surgical removal
of breast tissue. Until another reliable risk-reducing
measure is developed, risk-reducing surgery will re-
main a mainstay of management in women at very
high risk who want to reduce substantially their
chances of developing breast cancer.
Genetic predisposition
The presence of a significant family history is the
strongest risk factor for the development of breast
cancer. Even at extremes of age, the presence of
a BRCA1 mutation confers significant risks. A
25-year-old woman who carries a mutation in
BRCA1 has a greater risk of developing breast
cancer in the following decade than a woman aged
70 years in the general population. About 4–5% of
breast cancer is thought to be due to inheritance of
a high-penetrance, autosomal-dominant, cancer-
predisposing gene.1,2
Multiple primary cancers in one individual or related
early-onset cancers in a family pedigree are highly
suggestive of a predisposing gene. It is thought that
over 25% of breast cancers in women under 30 years
of age are due to mutation in a dominant gene, com-
pared with less than 1% in women who develop the
disease over 70 years.2 It has recently been found that
at least 27% of breast cancers under 30 years of age
are due to mutations in the known high-risk genes
BRCA1, BRCA2 and TP53. Nonetheless, risk is still
largely based on family history and the detection rate
for mutations in isolated breast cancer cases even at
very young ages is considerably less than 10%,6 al-
though sporadic grade 3 triple-negative cancers have
a little over a 10% chance of a BRCA1 mutation in
women under 40 years of age.7
There are few families where it is possible to be
certain of a dominantly inherited susceptibility.
However, the Breast Cancer Linkage Consortium
(BCLC) data suggest that in families with four or
more cases of early-onset or bilateral breast can-
cer, the risk of an unaffected woman inheriting a
­mutation in a predisposing gene is close to 50%.
Inheritance of a germline mutation or deletion
in a predisposing gene predisposes to early-onset,
and frequently bilateral, breast cancer. Certain
mutations also confer an increased susceptibility to
other malignancies, such as ovary (BRCA1/2) and
sarcomas (TP53)3–5 (Table 8.1).

Chapter 8
128
These studies have estimated that the majority of
such families harbour mutations in BRCA1 or
BRCA2, especially when male breast cancer or ovar-
ian ­cancer is present. In breast-only families, the fre-
quency of BRCA1/2 involvement falls to below 50%
in  four-case families.8 Family and epidemiologi-
cal studies have demonstrated that approximately
70–85% of BRCA1 and BRCA2 mutation carriers
develop breast cancer in their lifetime, although the
risk is a little lower for BRCA2.8–11 The very low
figures published on small numbers of families from
population studies have now been addressed by a
meta-analysis,11 which gives risks to 70 years of age
of around 70% for BRCA1 and 55% for BRCA2.
The chances that a family with a history of breast
and/or ovarian cancer harbours mutations in
BRCA1 or BRCA2 can be assessed from ­computer
models.12–14 We have recently validated these
­models using a dataset of 258 patients and their
samples tested for BRCA1/2 mutations. We found
that at the lower levels of likelihood for mutations,
the computer models substantially overpredict the
presence of mutations, particularly for BRCA1.15
The Manchester manual model was much better
at predicting a mutation in both genes and indeed
was better than other manual models (Table 8.2).
Further indicators for the presence of a BRCA1 mu-
tation within a family are grade and oestrogen re-
ceptor status. BRCA1 tumours are more frequently
grade 3 and oestrogen receptor negative or triple
negative, and often have a medullary-like histol-
ogy.16 Further studies incorporating pathology in-
formation into risk models such as the BOADICEA
have improved their prediction accuracy.17 Ovarian
cancers that develop in BRCA1/2 families are nearly
always non-mucinous epithelial cancers.18
Gene
Other
­tumour % of
susceptibility
Population
frequency
Proportion
of breast
cancer
Proportion
of HPHBC
Proportion
of ­familial
breast
­cancer risk
Lifetime risk
in women
(RR)
BRCA1 AD
Ovary/prostate
colorectal
0.1%
1.5%
40%
5–10%
60–85%
BRCA2 AD
Ovary/prostate
Pancreas HoZ
Fanconi (AR)
0.1%
1.5%
40%
5–10%
50–85%
TP53
Sarcoma, glioma
0.0025%
0.02%
2%
0.1%
80–90%
LFSPD
Adrenal





PTEN
Thyroid
0.0005%
0.004%
0.3%
0.02%
25–50%
Cowden's AD
Colorectal





CHEK2
Colorectal, prostate
0.5%
0.5%
0%
2%
18–20% (2.0)
ATM
HoZ (AR)
0.5%
0.5%
0%
2%
20%
AD and AR
Lymphoma,
leukaemia





STK11 AD
Colorectal
0.001%
0.001%
0.6%
0.04%
50%
BRIP1
HoZ Fanconi (AR)
0.1%
0.1%
0%
0.4%
20% (2.0)
PALB2
HoZ Fanconi (AR)
0.1%
0.1%
0%
0.4%
20% (2.0)
RAD51C
HoZ-Fanconi (AR)
0.1%
0.1%
0%
0.2%
14–20%
RAD51D
HoZ-Fanconi (AR)
0.1%
0.1%
0%
0.2%
14–20%
18 SNPs from
GWA
FGFR2 TRCN9,
30–46%
0.5–1%
0%
10%
11–13%
MAP3K, LSP1,
8q128424800, etc.




(1.1–1.3)
Totals

80% for any
5%
83%
35%

Table 8.1  •  Breast cancer genes: frequency and proportion of risk
AD, autosomal dominant; AR, autosomal recessive; GWA, genome-wide association studies; HeZ, heterozygous; HoZ, homozygous:
HPHBC, highly penetrant hereditary breast cancer (e.g. more than three affected relatives); LFS, Li–Fraumeni syndrome; RR, relative risk;
SNP, single nucleotide polymorphism.

The genetics of breast cancer, risk-reducing surgery and prevention
129
The likelihood of identifying a BRCA1/2 mutation
should not be confused with the ability to detect a
mutation if one is present in the family. No single
technique is able to detect all mutations. Even by
sequencing the entire gene (exons and intron/exon
boundaries), the detection rate only equates to
about 75%. If a strategy is added to detect large
deletions or duplications in BRCA1, this can boost
detection to around 95%.19
The proportion of breast/ovarian cancers attribut-
able to BRCA1 or BRCA2 depends on the ethnic
origin of families. Many countries or ethnic groups
have particular founder mutations that are not
seen in other populations. In countries with a small
founder population, very few mutations may ac-
count for the vast majority of breast cancer families,
such as in Iceland.
Populations that are more outbred, such as the UK,
have larger numbers of mutations and founder mu-
tations occur at lower frequencies. In the past, some
laboratories concentrated on the large exons (exon
11 in both genes and exon 10 in BRCA2) and the
smaller exons commonly reported to be involved,
such as exons 2 and 20 in BRCA1. This cuts down
the number of polymerase chain reactions ­using the
protein truncation test (PTT) to as little as five for
BRCA1 and four for BRCA2. However, this strat-
egy reduces the sensitivity of identifying mutations
down to as little as 50%.19 With the great strides
made in reducing cost and time of mutation search-
ing using next generation sequencing these older
strategies are now outdated.
Genetic testing
Once a mutation in a predisposing gene like
BRCA1 or BRCA2 has been identified in a family,
definitive genetic testing is possible. This can then
more accurately inform women of their risks and
give them an informed choice of different options,
including risk-reducing surgery. Undertaking mu-
tation analysis on an unaffected individual (with-
out checking an affected relative), particularly in
a breast cancer-only family, is problematic. Whilst
identifying a pathogenic mutation will confirm a
high risk, the absence of a mutation will not ex-
clude the possibility that other genes or even a
mutation refractory to the mutation screening
techniques used are present. Although other genes
are now being identified (see Table  8.1), many
more remain to be found and screening for muta-
tions is not clinically useful outside of BRCA1/2
and in certain circumstances TP53. Nevertheless,
the outcomes of genome-wide association studies
indicate that all breast cancer cases will carry at
least one risk allele.21,22 Once all the lower risk al-
leles have been found a definitive genetic test can
then be developed.

BRCA1
BRCA2
Female breast cancer <30 years
6
5
Female breast cancer 30–39 years
4
4
Female breast cancer 40–49 years
3
3
Female breast cancer 50–59 years
2
2
Female breast cancer >59 years
1
1
Male breast cancer <60 years
5 (if BRCA2 tested)
8
Male breast cancer >59 years
5 (if BRCA2 tested)
5
Ovarian cancer <60 years
8
5 (if BRCA1 tested)
Ovarian cancer >59 years
5
5 (if BRCA1 tested)
Pancreatic cancer
0
1
Prostate cancer <60 years
0
2
Prostate cancer >59 years
0
1
Table 8.2  •  Scoring system for identification of a pathogenic BRCA1/2 mutation
Scores for each cancer in a direct lineage are summed. A score of 10 is equivalent to a 10% chance of identifying a mutation in each gene.
The Ashkenazi Jewish population has three
founder mutations: 185delAG and 5382insC in
BRCA1, and 6174delT in BRCA2.16 The three
mutations are found in over 2% of the Ashkenazi
Jewish population. One study showed that one
of the three mutations was present in 59% of
high-risk families.20

Chapter 8
130
Breast cancer risk estimation
Where there is not a dominant family history or it is
not possible to identify a mutation in BRCA1/2, risk
estimation is based on large epidemiological studies,
which give a 1.5- to 3-fold relative risk with a fam-
ily history of a single affected relative.1,2 Clinicians
must be careful to differentiate between lifetime and
age-specific risks. Some studies quote a ninefold or
greater risk associated either with bilateral disease
in a mother or with severe atypical hyperplasia.
However, these risks are time limited and if these
at-risk individuals are observed for many  years,
their relative risk is reduced over time.23 Clearly, if
one uses these risks and multiplies them against the
lifetime incidence of 1 in 8–12 then some women
will apparently have a greater than 100% chance of
having the disease. Risks importantly do not multi-
ply and may not even be additive. The best way to
assess risk is to take the strongest risk factor, which
in most cases is nearly always the family history. If
risk is assessed on this alone, minor adjustments can
then be made for other factors. It is arguable whether
these other factors have any major effect on an 80%
penetrant gene other than to speed up or delay the
onset of breast cancer. Therefore, we can only really
assume an effect on non-hereditary elements of risk.
Although studies do point to an increase in risk in
family history cases associated with certain factors,
these may just represent an earlier age expression
of the gene. Generally, therefore, non-mutant gene
carriers will have risks somewhere between 40–45%
and 8–10%, although lower risks are occasion-
ally given. Higher risks are only applicable when a
woman at 40–45% genetic risk is shown to have a
germline mutation and to have inherited a high-risk
allele or to have proliferative breast disease.
These programs take into consideration varying per-
mutations of age of onset of diagnosis, number of af-
fected and unaffected women, and hormonal factors;
as a consequence, different programs result in differ-
ent risk estimations. The Gail model does not take
into account age of relatives or second-­degree rela-
tives. A newer model, the Tyrer–Cuzick,27 incorpo-
rates the majority of the currently known risk factors.
A major deficiency of current genetic models is the
assumption that all inherited breast cancer is due
to a single high-risk dominant gene or two genes
(BRCA1 and BRCA2). The problem this causes in
a program like BRCAPRO is that in order to obtain
an accurate assessment for identifying a BRCA1 or
BRCA2 mutation in a family, all other potential
genetic factors are overlooked. Therefore, while
BRCAPRO provides reasonably accurate estimates
for the presence of BRCA1/2 mutations in high-
risk families,12 its ability to predict breast cancer
incidence is substantially hampered in smaller ag-
gregations of breast cancer. Variation in their value
in different ethnicities has also been found.28–30 We
have recently found that BRCAPRO underestimates
the risk of breast cancer in moderate/high-risk fami-
lies by about 50%.31 The most accurate computer
model was the Tyrer–Cuzick model, although a
manual model incorporating the Claus tables and
data from the BCLC and adjustment for hormonal
and reproductive factors was similarly accurate.
A fuller explanation of the manual model25,31 and a
detailed review32 are available elsewhere.32
Management options
Management options available to reduce the risks of
developing breast cancer for women at high lifetime
risk due to their family history or for those women
known to be carrying a mutation in BRCA1/2 are
limited. Screening with mammography or magnetic
resonance imaging (MRI) is one option but this
detects cancer, it does not prevent it. Therefore,
imaging surveillance can be combined with che-
moprevention. However, many women consider or
undergo risk-reducing mastectomy (RRM) if found
to be at high risk, e.g. mutation carriers for BRCA1
or BRCA2. The efficacy of surgical procedures for
reducing the risk of breast cancer is controversial
but of proven benefit,33,34 although it would appear
that the residual risk of breast cancer depends on
the amount of residual breast tissue following the
surgical procedure. It would be ideal to perform a
prospective randomised clinical trial where women
Within Europe, risk estimation in the family
history setting is based mainly on the Claus
dataset.2,24,25 However, within the USA, the Gail
model of risk estimation is widely used.26 As well
as these datasets allowing estimation of risk,
there are specific computer programs available,
including Tyrer–Cuzick,27 Cyrillic, BOADICEA and
BRCAPRO.14

The genetics of breast cancer, risk-reducing surgery and prevention
131
with the same risk were randomised to either in-
tensive surveillance or prophylactic surgery, but it
would be difficult to recruit women for this type
of trial and so it is unlikely to happen. Recent
work suggests that more women are considering
RRM,35,36 although uptake rates even for BRCA
mutation carriers vary enormously, with a much
lower uptake in Israel and southern Europe, almost
certainly due to different cultural beliefs, protocols
and availability.36 Protocols should be in place to
deal with requests for RRM at all cancer genetics
and oncoplastic clinics. It has been suggested that
surgery does increase life expectancy in BRCA1 or
BRCA2 mutation carriers.37
Genetic counselling and the
family history clinic
Breast cancer family history clinics started to be
established in the UK in 1987,42,43 and these clinics
are now established across Europe, North America
and are now also emerging in Asia.44,45 Genetic
counselling sessions and family history clinics are
important not only to provide a means to select
suitable individuals for genetic testing, but also
to aid decision-making in individual women on
surveillance and preventative measures. They are
generally administered by consultants in medical
oncology, clinical genetics and breast surgery, often
with a multidisciplinary approach and with close
involvement of radiologists and a psychiatrist/
psychologist. At these clinics unaffected women
at increased risk of breast cancer are assessed as
to their lifetime and shorter-term risks of breast
cancer development. After assessing risk, women
are presented with a number of choices including
regular surveillance, usually with a combination
of clinical examination, mammography, ultraso-
nography and in some circumstances breast MRI46
that commences between 20 and 40 years depend-
ing on the age of onset of cancers in the family and
the overall risk. Women are generally divided into
three risk groups: average, moderate and high risk.
It is only in the high-risk group that RRM should
be considered. This usually equates to a lifetime
risk of 1 in 4 (25%) or greater. As a rough guide,
this equates to having a heterozygote risk of 1 in 4
with two relatives, including one first-degree rela-
tive, with breast cancer diagnosed below 50 years
of age or three affected relatives under 60 years.
All affected relatives should be first-degree rela-
tives or related through a male.
In a survey of 10 European centres,42 only three
(Manchester, Edinburgh, Heidelberg/Dusseldorf)
routinely mentioned the possibility of RRM to
women with a lifetime risk of 1 in 4 or greater. This
information is often only given as a statement of
the availability of the procedure as an option for
prevention of breast cancer. This allows women to
extend the discussion if they wish to do so, or to
state that they are not interested in surgery. Many
centres only mention risk-reducing surgery to po-
tential mutation carriers undertaking a genetic test.
Indeed, there is a cultural shift across Europe from
north to south, with RRM being less acceptable
to both physician and patient as one moves south-
ward.47,48 In the USA, in centres where mastecto-
mies for benign breast disease were commonplace
in the 1970s and 1980s,38 there appears to be less
enthusiasm for mastectomy now even among gene
mutation carriers.49 What is absolutely clear is that
adequate preparation of a woman contemplating
RRM is essential.
The RRM protocol
Women who wish to consider RRM should be given
time to consider the procedure thoroughly prior to
making the decision. In Manchester, a protocol is
in place for women who are assessed as at high risk
who would be suitable for RRM despite not having
certain knowledge of mutation status. For example,
an individual's calculated lifetime risk may be 40%,
but a recognised gene mutation may not have been
identified in the family. This exact same protocol
may not be offered in other centres but the general
principles of counselling apply. In general, most
centres will offer multiple sessions of discussion of
available surgical procedures and counselling. Most
women would be offered a further appointment at
least 1 month later. This not only gives the women
The first study to demonstrate that women
with a high risk of breast cancer can significantly
reduce their subsequent incidence of the disease
with RRM was published in 1999.38 This was
followed by a Dutch study that confirmed risk
reduction in those at highest risk (BRCA1/BRCA2
carriers).39 Current evidence would suggest that
RRM is associated with an approximately 90–95%
reduction in risk.40,41

Chapter 8
132
time to consider more fully all options but also
­allows time for them to discuss it with appropri-
ate members of their family. The mean time interval
from a personal genetic diagnosis to the date of sur-
gery of RRM is approximately 9 months.50 Usually
the partner or a family member selected by the pa-
tient is encouraged to attend the clinic session to
help decision-making. At the second appointment,
with a geneticist or oncologist, a basic description
of the surgery is provided, including the potential
residual risk of different procedures. It is empha-
sised that a residual breast cancer risk and com-
plication rates from surgery are still present after
RRM and may be higher if the surgery preserves the
nipple–areola complex (NAC). Options of simulta-
neous breast reconstruction can also be discussed.
It is important to prepare the patient for the likely
consequences of mastectomy including pain and
any possible complications that, if they occur after
breast reconstruction, may result in a poor cosmetic
result, as well as considering the impact upon her
personal life and family dynamics. Because of po-
tential pitfalls such operations should only be un-
dertaken by surgeons highly skilled in RRM and its
possible complications, to optimise both oncologi-
cal and aesthetic outcomes.
When possible, a living affected member should be
the first to undertake genetic testing as this provides
more information on the underlying genetic struc-
ture of the family.25,51,52 A time scale for genetic test-
ing is discussed, and the woman is asked to consider
the potential impact of proceeding with surgery,
particularly if she then undergoes genetic testing
and finds that she does not in fact carry the caus-
ative mutation. It is also emphasised that the genetic
risk of breast cancer decreases with age and that
the remaining risk of breast cancer if the woman is
older (>40 years) and has not developed breast can-
cer becomes lower than the lifetime risk.25 Indeed,
a mutation carrier for BRCA1 may have no more
than a 50% risk of breast cancer in her remaining
lifetime if she has reached 50 years, but this is still a
substantial personal risk. Psychological assessement
and counselling should be arranged for women who
are considering proceeding.
The whole process, from first consultation to the
surgical procedure itself, usually takes between 6
and 12  months. This time delay is deliberate; in
most centres the greatest delay is at the beginning
of the protocol in order to allow women time for
the decision-making process. If the protocol is run
concurrently with a decision for predictive genetic
testing, then the wait will generally be shorter.
The full protocol of two sessions at the family his-
tory clinic, a session with a psychiatrist and ses-
sions with the surgeon was established in 1993 in
Manchester. The major difference between this pro-
tocol and that offered by some other centres both
locally and internationally is that RRM in other
centres is offered only when raised by the patient,
and it is generally only offered in these centres
when a woman is proven to be a BRCA1/2 muta-
tion carrier. Even with a proven mutation carrier no
centre actively recommends surgery, but offers this
as part of a range of choices. The incorporation of
counselling during decision-making and treatment
has been shown to improve psychological and so-
cial outcome.54,55
There are various approaches of surgery that could
be recommended to the patient, including nipple–
areola-sparing mastectomy with an option of breast
reconstruction, depending on the centre, and the
women's preference, as well as breast size and shape
of the individual. Availability of appropriate surgeon
expertise is paramount. There is no clear consensus
in terms of the surgical procedure recommended in
women who decide on surgery and a detailed surgi-
cal consultation should aid the woman's decision.
Surgical consultation
The aim of risk-reducing surgery is not only to re-
duce cancer risk and breast cancer mortality, but
also to reduce the psychological distress and anxiety
of an individual.56 For unaffected mutation carri-
ers RRM reduces lifetime risk of breast cancer to
less than 5%.57,58 However, any surgical procedure,
particularly in a preventative setting, warrants
Confirmation of breast cancers in the family
must be sought proactively if this has not already
been done. This ensures that risk assessment is
as accurate as possible. The Manchester group
has previously reported the presence of factitious
histories within some families where women have
fabricated their family history in order to obtain
surgery, or are implicated innocently as being at risk
by another family member who has promoted an
inaccurate family history.53

The genetics of breast cancer, risk-reducing surgery and prevention
133
a balanced discussion of its benefits and risks. Due
to lack of level I evidence from randomised con-
trolled clinical trials, recommendations are usually
based on cohort studies of prophylactic surgery.59,60
Moreover, to date, although risk of breast cancer is
reduced there are still no data that show statistically
significant improvement in survival after RRM. It
is also important that when a women embarks on
such a decision, a full understanding of the surgery
involved is achieved and the woman understands
that risk reduction of cancer is never 100%. Risk
reduction surgery is not a minor cosmetic proce-
dure but major surgery, and hence the nature and
extent of the surgery and possible complications
need to be considered. The expected cosmetic result,
changes in the patient's breast sensation and also
the impact of RRM on a patient's social life should
be addressed. The whole range of evolving surgical
techniques that can be offered should be discussed
thoroughly before a decision is made for surgery.
In order to properly select suitable individuals for
RRM, at least two detailed surgical consultations
are needed to discuss the types of mastectomy and
breast reconstruction procedures that are available.
The techniques, limitations, outcomes and potential
complications, and photographs of a range of aes-
thetic outcomes should be shown. It must be em-
phasised that there is still a small chance of getting
cancer after RRM and that subjectively the breasts
may look and feel different from the original breasts
even if a successful surgical outcome is achieved.
Time should be given for the women to digest this
information. Consultations should involve a breast
oncoplastic surgeon, plastic surgeon if appropriate
and also a breast nurse specialist. More intimate is-
sues including quality-of-life concerns, changes of
body image and impact on sexual relationship with
her partner may result in further questions follow-
ing surgical consultation.61 Before discussing details
of options for surgery, during the consultation ses-
sion it is important to identify any women where
RRM may not be advisable. There are relative con-
traindications to RRM taking place (see Box 8.1).
The decision of which surgical option to choose
will vary between individuals (see Box 8.2).62 For
some women a traditional total simple mastectomy
without reconstruction may offer what she wants
as it reduces risk and can be cosmetically accept-
able if performed appropriately (see Chapter  5),
whereas for others NAC-sparing mastectomy with
­reconstruction is the only acceptable aesthetic out-
come. Skin-sparing mastectomy (SSM) has already
been shown to be as oncologically safe as total simple
mastectomy on selected patients, but the data avail-
able are mainly from patients with existing breast
cancer. There are no specific data for prophylac-
tic surgery using SSM, but it does appear to be an
• Risk of breast cancer is not high or confirmed
• Genetic test has been performed but results are still
unavailable
• Unreliable family history
• Munchausen syndrome (Factitious history)
• Risk of surgery outweighs its benefit
Psychosocial related
• Not personal choice but choice of family members
and partner
• Unrealistic expectation of aesthetic result
• Psychiatric disorders
The ability to understand the procedure
• Choice of surgery is for cosmetic rather than
oncological reasons
• Unrealistic expectation of the amount of risk reduction
possible
Box 8.1  •  Absolute and relative contraindications to
risk-reducing mastectomy
• Simple total mastectomy (STM)† with or without
breast reconstruction
• Skin-sparing mastectomy (SSM)‡ with or without
breast reconstruction
• Nipple–areola complex-sparing mastectomy (NSM)§
with or without breast reconstruction
• Areola-sparing mastectomy (ASM)§ with or without
breast reconstruction
Box 8.2  •  Choice of surgical technique for risk-reducing
mastectomy*
Reproduced from Guillem JG, Wood WC, Moley JF et al.
ASCO/SSO review of current role of risk-reducing surgery in
common hereditary cancer syndromes. J Clin Oncol 2006;
24(28):4642–60.
*All of the above types of mastectomies involve the removal of
breast tissue and vary with respect to the skin that is spared.
†Total mastectomy removes an ellipse of skin including the
nipple–areola complex.
‡SSM preserves the majority of the skin but removes the
nipple–areola complex.
§NSM and ASM preserve the nipple and areola respectively,
and preserve more skin.

Chapter 8
134
­acceptable approach oncologically.63,64 Non-SSM,
also known as subcutaneous mastectomy, evolved
due to psychological studies that found that the feel-
ing of mutilation is increased after removal of the
NAC when performing mastectomy.65 It is unsafe
to compare directly data from women who have
been treated for breast cancer with those who have
not; however, there have been controversies behind
the safety of saving the NAC, as occult tumour
­involvement behind the NAC in mastectomy speci-
mens in cancer patients has been reported to occur
in 0–50% of cases.66–68 However, many of these
studies were performed more than two decades ago
when significant amounts of breast tissue were left
behind the nipple and there are new data indicat-
ing that for selected individuals nipple-sparing mas-
tectomy (NSM) is oncologically safe. Moreover, it
is likely that, formerly, case selection was less well
planned and with improvement of case selection of
patients who are deemed more suitable for NSM,
either by clinical presentation or after MRI with use
of intraoperative frozen section to exclude patients
with nipple involvement, it is likely that long-term
results would be favourable.69–71 There is a risk of
nipple–areola complex necrosis of about 5–15%
when performing NSM, which can be partial or
complete, and this is more common in smokers (see
Chapter 5). In general, partial necrosis usually heals
without further surgical intervention. There is a
proportion of women who suffer nipple sensation
loss of 25%.72–74 Loss of nipple projection and de-
pigmentation of the areola skin are also common
problems with NSM. The improvement of psycho-
logical outcome from NSM65 makes this the option
of choice for most women considering RRM.
Various techniques have been suggested as inci-
sional options for NSM.74
Incisions for nipple-sparing
mastectomy (Figs 8.1–8.6)
In a study by Esserman and colleagues, it was found
that NAC necrosis was higher when an incision
crossing the NAC was used (18%).74 If the inci-
sion spanned less than one-third of the circumfer-
ence of the areola the results were good. Those that
cover more than one-third of the circumference are
likely to compromise the blood supply of the nip-
ple, which can result in loss of nipple–areola skin.
Inframammary incisions were found to be more
suitable for women with small breasts, as this inci-
sion allows only limited exposure of the upper part
of the breast, being particularly problematic if per-
formed in women who have larger breasts. A radial
incision in this study provided the best access for
breast tissue removal and was most likely to main-
tain NAC viability, but can result in nipple deviation
in the direction of the incision. If ­reconstruction is
planned, then the choice of incision is even more
important and should be based on the size of the
breast and the degree of ptosis.
a
b
Figure 8.1  •  (a) Skin-sparing dissection with removal of
the nipple and areola skin and replacement of the nipple
alone or the nipple–areola complex as a free graft. (b)
Submammary/inframammary incision.
Figure 8.2  •  Batwing incision to reduce the upper skin
and elevate the nipple.

The genetics of breast cancer, risk-reducing surgery and prevention
135
Areola-sparing mastectomy (ASM) has also been pro-
posed as an option to NSM, as in theory it is the ducts
that transverse the nipple that can harbour occult meta-
statis and not the areola disc, which is more similar to
‘skin’.34 Hence, over recent years this has also become
an option for women who choose to have a mastectomy.
Risk-reducing surgery and
breast reconstruction
Mastectomy can be a mutilating surgery for many
women and so during the last century there has been
increased use of reconstruction for women who opt
for mastectomy. This is even more relevant for the
group of high-risk women who opt for RRM, who
have not themselves had breast cancer, and who
need long-term reconstruction of functional and
aesthetic excellence. The need for more and better
breast reconstruction options after mastectomy has
resulted in an increase in the number and types of
different reconstructive techniques to achieve the
best aesthetic outcomes with a more personalised
approach based on a woman's breast size, desired
outome and ­technical feasibility (see Box 8.3).
Figure 8.3  •  Incisions across or below the nipple.
Figure 8.4  •  Incisions above the nipple with or without
skin crease lateral extension.
Figure 8.5  •  Radial or skin crease incision.
Figure 8.6  •  Wise pattern risk-reducing mastectomy
planning.

Chapter 8
136
Reconstructions after RRM can be performed im-
mediately or in a staged fashion. In general, unless
contraindicated, immediate reconstruction should
be performed as it avoids the woman having a pe-
riod of time without a ‘breast’ and it allows skin
to be spared, which improves the final cosmetic re-
sult (Fig. 8.7). Although most reconstructions pro-
duce satisfactory results, it is not uncommon for a
patient to have expectations that there will be no
visible scars. Moreover, providing patients with
photographs of possible complications is an impor-
tant part of informing the patient, as is providing a
specialist nurse to liaise with the woman and to ad-
dress further questions that the woman may have.
Sharing experience with others who have under-
gone the procedure may also help to better prepare
an individual when deciding on RRM and breast
reconstruction.
In women with large breasts, the skin envelope
may need to be reduced when performing breast re-
construction (Figs 8.8 and 8.9). The placement of an
acellular dermal matrix can also be used in addition
to fat injection to achieve a better aesthetic result.71
Autologous myocutaneous flaps use natural tissue,
and give women the feeling that they are using living
tissue and have a warm soft consistency that can be
more realistic. Expertise in oncoplastic and plastic
surgery is required to decrease complication rates
when microvascular anastomoses are warranted.
The use of implant devices after RRM seems a
simpler option compared with the transfer of myo-
cutaneous flaps but complications are common
and considerable skill and expertise is required to
get good, consistent results. There are different
types of prosthesis in relation to shape and con-
tour. Prostheses can be permanent or allow expan-
sion, with saline being injected gradually into the
­expandable chamber of the prosthesis until the de-
sired volume is achieved. These help in providing a
natural ‘breast’ projection and may result in better
contour in the upper breast.75 Anatomical expand-
ers permit more rapid expansion and result in lower
pressures within the implant, appear less likely to
migrate and cause less chest deformity. Silicon gel
implants are available in a range of specifications
and gel types, to allow a more natural look and
feel. Implants are usually placed under the chest
wall muscle and, combined with well planned
and ­carried out surgery, can give a good aesthetic
­outcome. Complications from such surgery include
Autologous myocutaneous flaps
Most commonly used:
• Transverse rectus abdominis flap (TRAM)
• Latissimus dorsi flap (LD)
• Rectus muscle-sparing deep inferior epigastric
perforator flap (DIEP)
Less commonly used:
• Buttock flaps including inferior gluteal artery perforator
and superior gluteal artery perforator flaps
• Gracilis-base thigh flaps
Myocutaneous flaps can be de-epithelialised if NSM or
SSM techniques are used for mastectomy
Implants
• Permanent implants
• Expander/implants (Becker expander/implants)
• Expanders followed by implants
Combination of autologous flap with implant
• LD flap with implant
Box 8.3  •  Options for women who choose to have RRM
with reconstruction
Figure 8.7  •  Horizontal/oblique risk-reducing mastectomy (RRM) before (a) and after (b) operation.
a
b

137
Figure 8.8  •  (a) Wise pattern risk-reducing mastectomies with nipple reconstructions. (b–d) The same patient 10 years
later, with left lateral view (c) and right lateral view (d).
a
c
b
d
c
d
e
Figure 8.7, cont'd  •  (c–e) The same patient 15 years after RRM and implant reconstruction.

Chapter 8
138
implant loss, haematoma, wound infection and skin
flap necrosis, and the rate has been quoted as greater
than 10%. For women who choose to have NSM,
the use of expanders or Becker expander/prostheses
allows gradual expansion to minimise skin tension
and is associated with lower infection and implant
loss compared with fixed-volume implants, particu-
larly if the implants are of a volume greater than the
original breast size.74 Use of permanent expander
prostheses with detachable valves is associated with
low infection rates and good recovery in women
who have RRM and reconstruction.76 Alternative
incisions have been proposed when performing
RRM with reconstruction for high-risk women and
these include the inverted drip incision.77 Implants
can also be combined with a myocutaneous flap and
acellular dermal matrix. The overall ­complication
rate using a direct-to-implant immediate breast
­reconstruction using human acellular dermal ­matrix
(ADM) or ADM from porcine or bovine skin or
­bovine pericardium has been reported to be low, at
3.9% in some series (implant loss 1.3%, skin necrosis
1.1%, haematoma 1.1%, human acellular dermal
matrix exposure 0.6 %, capsular contracture 0.4%,
and infection 0.2%).78 More recent reports using
non-human acellular dermal matrices report an
implant loss rate closer to 10%. There is a higher
rate of seroma, infection and implant loss compared
to when ADM is not used, but the aesthetic results
are superior with ADM (see Chapter 9). RRM with
breast reconstruction is considered a reasonably
safe and acceptable procedure for risk reduction un-
til other risk reduction methods become available.
If the NAC is removed during RRM, the NAC can
be reconstructed with the areola tattoed. There has
also been a description of nipple grafting, in par-
ticular if the areola is kept and the nipple is retrans-
planted to the reconstructed breast.76
Follow-up
After risk-reducing surgery, women should have
a prolonged follow-up protocol and should be re-
viewed annually at a multidisciplinary clinic. Long-
term aesthetic outcome should be assessed and, if
necessary, surgical interventions offered to improve
the costmetic outcome. Problems do arise and, when
necessary other members of the team should be in-
volved. Clinical examination by palpation of the
breasts is considered to be adequate, as remaining
breast tissue is very superficial in all types of surgical
procedure.
Uptake
Data from Manchester, UK79 show that 6% of women
who are at a 1 in 4 (31/902) lifetime risk or above
seek further advice about RRM and 1.8% (16/902)
have undergone surgery; this rises to 6% (49/798) in
those at 40–45% lifetime risk. Although the uptake
in BRCA1/2 carriers tended to be early, there was a
continued increase in uptake so that by 7 years the ac-
tuarial uptake for RRM for BRCA1 carriers was 60%
and for BRCA2 carriers was 43%. Results from the
Netherlands show a ­similarly high uptake (52%).39
Thus far, 35 mutation carriers in our series and several
in the Dutch series that initially opted not to have sur-
gery have developed breast cancer, whereas only two of
the operated cases have. Newer research including non-
European/American cohorts from Asia have found
that RRM is generally considered only in women
who already have breast cancer and decide to opt for
completion mastectomy and contralateral prophylac-
tic mastectomy, although the uptake of prophylactic
salpingo-oopherectomy is slightly higher. There is also
a proportion of women who consider risk-reducing
surgery after a period of intensive surveillance.44
Figure 8.9  •  Wise pattern risk-reducing mastectomy
after nipple–areola reconstruction.
The mean expected rate of breast cancer for our
cohort of high-risk women is 1% annually, reflecting
a lifetime risk that ranges from 25% to 80%. To
date, although RRM can reduce the risk of breast
cancer, it has not been proven to have a survival
benefit. It is unlikely there will be randomised trials
and hence more cohort studies will be necessary to
provide more data to support its use.

The genetics of breast cancer, risk-reducing surgery and prevention
139
Role of sentinel lymph node
biopsy in RRM
It has been suggested that as occult cancers are found
in 5% of prophylactic mastectomy specimens, to avoid
a second operation sentinel lymph node biopsy
(SLNB) should be performed when performing RRM.
However, the latest research has found that although
occult malignancy can be present in prophylactic mas-
tectomy specimens, it is rare for the occult carcinoma to
spread to the lymph nodes. A meta-analysis of available
research studies found that the rate of occult invasive
cancer was 1.7% and the rate of positive SLNB was
1.9%. Hence, it is concluded that SLNB should not be
performed during RRM of women without cancer but
may be considered if cancer is present (see chapter 7).80
Psychosocial consequences
of RRM
Surgery for high-risk women
with established breast
cancer
For women who are diagnosed with unilateral breast
cancer, there is a 2–5% risk of having cancer in the
contralateral breast. For BRCA mutation carriers,
studies have found that if breast-­conserving surgery is
performed, the 10-year cumulative incidence of ipsi-
lateral breast cancer recurrences is 27% for mutation
carriers versus 4% for sporadic controls. The 10-year
cumulative incidence of contralateral breast cancer is
25% in mutation carriers compared with 1% in spo-
radic controls.89 Hence, it is most likely that women
who are BRCA mutation carriers should consider
­mastectomy on the diseased breast and also consider
contralateral prophylactic mastectomy (CPM). CPM
can reduce contralateral cancer development by 90%,
but its effectiveness in preventing breast cancer mor-
tality is far from clear. Although most studies have
found good psychological outcomes and also satisfac-
tion in women who undergo CPM, the operation is
not risk free and complications related to the surgical
procedures, including breast reconstruction, do occur.
These factors all need to be addressed when consider-
ing a decision on CPM. Any contralateral procedure
can be delayed until treatment for the primary cancer
is completed. The prognosis depends on the primary
cancer tumour biology. A woman who is found to
have substantial lymph node involvement is unlikely
to benefit from CPM. Hence the management deci-
sion of this group of women should be decided at a
multidisciplinary meeting and the aim must be to pri-
oritise treatment of the primary malignancy.90
Individual circumstances vary widely; the decision
on how to proceed is individual to each patient.
Rates of contralateral mastectomy are high in gene
mutation carriers where the efficacy of contralateral
mastectomy is now well established. Proof that this
may save lives is now emerging.91–98
Bilateral risk-reducing
salpingo-oophorectomy
Bilateral risk-reducing salpingo-oophorectomy is
an option that can be undertaken in women with
BRCA1/2 mutations in order to reduce the risk of
ovarian cancer.
The majority of studies exploring the
psychological impact of RRM have found that
surgery is associated overall with fairly high levels
of satisfaction, reduced anxiety and psychological
morbidity amongst women who undergo this
procedure.81–88 This is particularly so when there
is support from family and friends.83 A number
of studies suggest that provision of presurgical
multidisciplinary support appears to have a bearing
on outcome, particularly in those who have initial
anxiety and negative psychological reactions. These
negative effects are usually related to surgical
complications and reduce with longer follow-
up. A minority of women do express regrets and
experience adverse psychosocial events following
surgery, including adverse emotional stability, self-
esteem and problems in sexual relationships.87
These women are often young, and if their family
history is attributable to a gene mutation, identified
or not, their personal risk of local recurrence or
development of a second primary cancer in the
same breast is higher than in women with sporadic
breast cancer; their risk of contralateral new primary
malignancy is also high.81–83
In addition to reducing the risk of ovarian cancer,
prophylactic salpingo-oophorectomy has also been
shown to decrease the risk of breast cancer in
women with a BRCA1/2 mutation by 46–56%.99

Chapter 8
140
If salpingo-oophorectomy is performed at a pre-
menopausal age, usually at about 40  years old,
particularly in BRCA1/2 mutation carriers, and if
hysterectomy is performed at the same setting, the
use of unopposed oestrogen as hormone replacement
therapy (HRT) can ameliorate symptoms of surgical
menopause and does not seem to increase the risk of
breast cancer.100,101 However, as long-term effects are
still not known, the effects of an early menopause and
doubts over long-term HRT use have to be considered
if the primary purpose is breast cancer prevention.
Bilateral risk-reducing oophorectomy in high-risk
women prior to the menopause will therefore de-
crease the risk of both breast and ovarian cancer.
Use of chemopreventive
agents
Selective oestrogen receptor
modulators (SERMs)
Four large trials with tamoxifen in high-risk women
without breast cancer have been undertaken, and
long-term follow-up information is now available. An
overview of these trials has shown a 43% reduction
in oestrogen receptor (ER)-positive invasive cancer,
but no impact on ER-negative disease. Importantly,
a reduced ­incidence has been seen in the period after
active treatment was completed, with an additional
38% reduction in  years 6–10. As side-effects were
minimal in the post-treatment period, the risk–­benefit
ratio has improved with longer follow-up and an
unanswered question is whether there is additional
benefit after 10 years of follow-up. The effectiveness
and side-effect profile of tamoxifen is now very well
understood and it is currently considered the agent of
choice for preventive therapy, especially in premeno-
pausal high-risk women or those with atypical hyper-
plasia or lobular carcinoma in situ (LCIS).
Another SERM, raloxifene, has been evaluated in
three randomised trials. In two of these trials breast can-
cer was not the primary end-point but nevertheless the
results showed a marked decrease in breast cancer inci-
dence with raloxifene. Early reports suggested a greater
benefit than tamoxifen. The most recent direct com-
parison with tamoxifen in the STAR trial at 81 months
indicated that the risk ratio of raloxifene:tamoxifen
was 1.24 for invasive cancer and 1.22 for non-invasive
disease. Adverse events were less common with raloxi-
fene: relative risk 0.55 for endometrial cancer, 0.19 for
endometrial hyperplasia and 0.75 for thromboembolic
events. Raloxifene for postmenopausal women thus
appears to have advantages compared with tamoxifen.
More recently, lasofoxifene and arzoxifene have
been investigated in randomised trials where the pri-
mary focus was on fracture prevention in osteoporotic
women. Both trials have shown a significant decrease
in ER-positive breast cancers with these agents.
None of the SERMs has demonstrated any impact
on ER-negative tumours, so that other approaches
are needed for this type of breast cancer.
Aromatase inhibitors
A reduction in contralateral breast cancer has been
seen in all adjuvant trials comparing an aromatase
inhibitor with tamoxifen or placebo, with an over-
all reduction of 50% compared to tamoxifen, sug-
gesting a potential 75% reduction overall. The use
of aromatase inhibitors in the preventive setting
is being tested in two randomised clinical ­trials in
­high-risk women without breast cancer but of course
is limited to the postmenopausal setting – which for
most women at high risk is past the age at which
they are more likely to make preventive decisions.
Acknowledgement
Thanks to Dr Louis Kwong, Jr for supplying the
original line drawings in this chapter.
Tamoxifen reduces breast cancer incidence by
40–50%93,102–105 and this is maintained in long-term
follow-up after cessation of treatment.105 However,
this reduction is almost exclusively a reduction in
oestrogen receptor-positive disease and whether
this translates into a reduction in cancers related
to BRCA1 mutations remains unclear. The NSABP
Study of Tamoxifen and Raloxifene (STAR) Trial
has shown that raloxifene is nearly as effective as
tamoxifen in reducing invasive breast cancer risk
and has fewer adverse side-effects.106 However,
there are no data available on the efficacy of
raloxifene for breast cancer risk reduction among
BRCA gene mutation carriers.
This can be seen from the risk of breast cancer in
unaffected women and in the contralateral breast
for those with breast cancer. Moreover, a recent
study has shown that prophylactic salpingo-
oophorectomy not only reduced the risk of breast
and ovarian cancer but also lowered all-cause
mortality, as well as breast cancer and ovarian
cancer specific mortality.57

The genetics of breast cancer, risk-reducing surgery and prevention
141
Key points
• Gene testing can be useful but may not be possible for many women with a strong family history
as no genetic mutation can be identified.
• Between 4% and 5% of breast cancer is due to high-penetrance cancer-susceptibility genes.
• BRCA1 and BRCA2 gene mutations result in breast cancer in young women, often bilateral.
• Familial breast cancer can be associated with ovarian and some other malignancies.
• Gail, Claus, Tyrer–Cuzick, BRCAPRO and BOADICEA models predict individual breast cancer risk.
• RRM decreases breast cancer incidence by over 90–95%.
• Common RRM approaches combine breast parenchymal removal with breast reconstruction.
• Breast reconstruction should be appropriate for individual breast morphology.
• RRM can produce profound relief of anxiety, but is major surgery and complications must be
avoided wherever possible.
• RRM should be undertaken by multidisciplinary specialised teams working within a protocol.
• Follow-up should ensure that results and outcomes are audited.
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