Breast conserving surgery with axillary dissection and adjuvant

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					Breast conserving surgery with axillary
dissection and adjuvant radiotherapy
versus modified radical mastectomy
(includes axillary dissection) and
adjuvant radiotherapy
  - An up-to-date evidence based discussion
     and review




                                          Dr CPG Nel

                           Registrar: General Surgery

                           Faculty of Health Sciences

                          University of the Free State



                                            July 2010
                                                                                                                                              Page |1




Index
Introduction ............................................................................................................................................ 3
Historical perspective and theory overview ........................................................................................... 4
Relevant anatomy ................................................................................................................................... 5
   The breast ........................................................................................................................................... 6
   The axillary dissection ......................................................................................................................... 6
   Lymphatics .......................................................................................................................................... 6
   Nerve supply ....................................................................................................................................... 7
Relevant pathology ................................................................................................................................. 7
   Ductal Carcinoma in Situ ..................................................................................................................... 9
   Invasive breast cancer......................................................................................................................... 9
   Grading of breast cancer: Histological Grade (G) ............................................................................. 10
   Staging of breast cancer.................................................................................................................... 11
Relevant oncology................................................................................................................................. 15
   Anatomy and the influence thereof on cancer spread and metastases ........................................... 15
       Primary Site ................................................................................................................................... 15
       Chest Wall ..................................................................................................................................... 16
       Regional Lymph Nodes.................................................................................................................. 16
       Metastatic Sites............................................................................................................................. 17
   Ipsilateral breast tumor recurrence .................................................................................................. 18
Clinical Trials ......................................................................................................................................... 18
   Review of Breast Cancer Clinical Trials Conducted by the National Surgical Adjuvant Breast Project
   .......................................................................................................................................................... 19
       National Surgical Adjuvant Breast Project B-04 ............................................................................ 19
       National Surgical Adjuvant Breast Project B-06 ............................................................................ 19
       National Surgical Adjuvant Breast Project B-21 ............................................................................ 20
       National Surgical Adjuvant Breast Project B-17 ............................................................................ 21
   LEVEL IA EVIDENCE: PROSPECTIVE RANDOMIZED SURGICAL TRIALS IN BREAST CANCER ............... 22
       1. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total
       mastectomy, and total mastectomy followed by irradiation ....................................................... 22
       2. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and
       lumpectomy plus irradiation for the treatment of invasive breast cancer. ................................. 23
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       3. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on
       local recurrence and 15-year survival: an overview of the randomised trials. ............................ 23
   Other trials ........................................................................................................................................ 24
Choosing what type of surgery to do .................................................................................................... 25
   Mastectomy as best choice............................................................................................................... 26
       Inability to deliver breast radiotherapy ........................................................................................ 26
       Multicentric disease ...................................................................................................................... 28
       Inability to achieve clear margins ................................................................................................. 28
       Age ................................................................................................................................................ 29
       Biologic subtypes of breast cancer ............................................................................................... 29
Breast conserving surgery ..................................................................................................................... 30
   History and physical examination ..................................................................................................... 31
   Mammographic evaluation ............................................................................................................... 31
   Pathological features influencing treatment choice ......................................................................... 32
   Patient preferences........................................................................................................................... 32
   Absolute and relative contraindications ........................................................................................... 33
       Absolute Contraindications........................................................................................................... 33
       Relative Contraindications ............................................................................................................ 34
   Indications and requirements for breast-conserving surgery .......................................................... 34
   Nipple/areolar sparing mastectomy ................................................................................................. 35
   BCS after Neoadjuvant therapy ........................................................................................................ 35
       Local treatment after neoadjuvant systemic therapy .................................................................. 37
   BCS and Locally advanced breast cancer .......................................................................................... 38
   Treatment of the Primary Site in Patients with Stage IV Breast Cancer ........................................... 39
   BCS & Receptor status ...................................................................................................................... 40
BCS & Ductal Carcinoma In-situ (DCIS) ................................................................................................. 41
Conclusion ............................................................................................................................................. 43
Research in the future .......................................................................................................................... 44
References ............................................................................................................................................ 45
Bibliography .......................................................................................................................................... 45
                                                                            Page |3




Introduction
Over the past 40 years, there has been a major change in the treatment of patients
with early breast cancer, with breast conservation surgery (BCS) coming to the
forefront as a viable option

Mastectomy, however is still widely used, especially for patients with large tumors
and small breasts, those patients with central lesions (although a central
lumpectomy is possible), tumor multicentricity, patient preference, or for the patient
with a contraindication to radiation treatment.

Guidelines for the loco regional treatment of primary breast cancer were last
published by the US National Institutes of Health in 1991. Since then, new surgical
and radio therapeutic techniques have been developed, clinical trials have provided
new evidence, and intriguing long-term effects have emerged from global
metadatabases. A revision of these guidelines is therefore necessary.

Since the early 1990s, a decline in breast cancer mortality has been observed in both
Western Europe and the United States because of the adoption of screening
mammography and the widespread use of systemic treatment. It has become
apparent that improved local control is also causally associated with improved breast
cancer survival, a paradigm shift in the understanding of this disease. An absolute
reduction in local recurrence at 5 years is associated in a 4:1 ratio with an absolute
survival advantage at 15 years. This information was not available when
recommendations for loco regional treatment were made in 1991. It is therefore
considered appropriate to critically appraise these recommendations and to consider
the impact of improvements in surgery, radiation therapy (RT), and systemic
treatments on local control. As the evidence base rapidly expands, it becomes vital
for surgeons involved in the treatment of patients with breast cancer to be aware of
the latest recommendations and to implement this in daily practice.



This review will attempt to discuss the evidence on which current recommendations
are based as well as an overview of breast conservation surgery, with the different
aspects involved. As this review does not entail any new research, an extensive list
of references and suggested reading material is provided at the end of the
document. It should be noted that this document encompasses an overview of the
topic, with additional information, which will not be part of the presentation at the
congress, but which is merely provided for completeness‘ sake.
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Historical perspective and theory
overview
No discussion on modified radical mastectomy versus breast conservation surgery
for breast cancer would be complete without a glance back in history and a
discussion of the theories involved.

In the latter part of the nineteenth century, there appeared to be a consensus that
breast cancer could be cured by surgical therapy. In 1894, surgeon William Halsted
popularized radical mastectomy as the treatment of choice for breast cancer based
on the theory that the disease spreads locally and through the lymphatics. This was
summarized by Keen in 1894: ‗‗. . . There is no question at all in the present day that
(breast cancer) is of local origin. In my early professional life, it was one of the
disputed points constantly coming up in medical society as to whether it was local or
from the first a constitutional disease, and whether the latter it was said that no
good could come from operating on the breast. But this question of local origin is no
longer confronting us. It is a settled thing, a point won, and women must be taught
that this brings hope and help to them‘‘ [1].

Almost 100 years later, Dr.Bernard Fisher, Head of the National Surgical Adjuvant
Breast and Bowel Project (NSABP), expressed the concept that breast cancer is a
systemic disease with haematogenous spread very early in the disease process. He
stated: ‗‗Breast cancer is a systemic disease at diagnosis. The metastatic phenotype
is either present or absent, but is not acquired over time. Variations in loco-regional
therapy are unlikely to affect survival substantially‘‘ [2]

Three dominant theories of breast cancer tumor progression have evolved: (1) the
Halsted paradigm, (2) the Fisher paradigm, and (3) the Spectrum paradigm. The
first, the Halsted paradigm, states that breast cancer follows an orderly progression,
from primary tumor to axillary lymph nodes, and then finally on to metastatic sites.
Intuitively, therefore, aggressive loco regional resection of tumor and regional
metastases would be paramount to achieving superior survival benefits over less
minimal surgery.

Halsted‘s theory that breast cancer is a local–regional disease in the early phase is
supported by the fact that one third of lymph-node-positive patients are cured
without systemic therapy with only surgery and/or radiation therapy. Therefore,
lymph node metastases occur independently from distant metastases and may be a
nidus of systemic disease. Clearly, not all patients with early breast cancer are cured
with radical surgery. In fact, approximately 20% of node-negative patients develop
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distant metastases, indicating haematogenous spread occurs independently from
lymphatic spread.

The second theory, the Fisher paradigm, contends that breast cancer is a systemic
disease at its inception and the only hope for definitive cure is by addressing the
micro metastatic burden of occult cancer.



Although Fisher‘s concepts will have an enduring effect on our understanding of
breast cancer biology, a decade into the twenty-first century there is again a focus
on the local therapy of breast cancer. This has been driven by evidence from the
overviews published by the Early Breast Cancer Trialists Group (EBCTG), which
clearly show that improved local control results in improved breast cancer survival.

The third and a more moderate, generally accepted viewpoint, however, is the
Spectrum paradigm, which is essentially a compromise between the Halsted and
Fisher paradigms: breast cancer may be but is not universally systemic at its
inception. Loco regional treatments are important because often a primary tumor or
nodal deposits occur before dissemination of metastases. This theory then argues
that the best chance for cure is achieved via loco regional and systemic treatment
through a multimodal approach for breast cancer patients of all stages.



Optimal breast cancer therapy must include probability assessment and
management of local–regional and distant disease, requiring in most of the cases
both local– regional and systemic therapy




Relevant anatomy
Only a basic summary of relevant anatomy is given here, as it is expected that the
reader has a fairly good understanding of the anatomy of the breast and
surrounding tissues. For a full detailed description of macro and micro anatomy of
the breast, including the blood supply, the reader is referred to a good anatomic
textbook. Sabiston‘s Textbook of Surgery provides a relatively concise summary of
the basic relevant anatomy of the breast for a surgeon and can be summarized as
follows:
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The breast
The mature breast lies in adipose tissue between the subcutaneous fat layer and the
superficial pectoral fascia. Between the breast and the pectoralis major muscle lies
the retromammary space, a thin layer of loose areolar tissue that contains
lymphatics and small vessels. During removal of the breast, the breast is separated
from the pectoral muscle in the plane of the retromammary space over the muscle.
Located deep to the pectoralis major muscle, the pectoralis minor muscle is enclosed
in the clavipectoral fascia, which extends laterally to fuse with the axillary fascia.
Dissection along the lateral border of the pectoralis minor muscle divides the
pectoralis fascia and exposes the contents of the axilla. Within the loose areolar fat
of the axilla are a variable number of lymph nodes, the amount of nodes depends on
the extent of dissection.



The axillary dissection
To standardise the extent of axillary dissection, the axillary nodes are arbitrarily
divided into three levels

Level I nodes are located lateral to the lateral border of the pectoralis minor muscle

Level II nodes are in the central axillary group and are located under pectoralis
minor muscle.

Level III nodes include the subclavicular nodes medial to the pectoralis minor
muscle.

The apex of the axilla is defined by the costoclavicular ligament (Halsted‘s ligament),
at which point the axillary vein passes into the thorax and becomes the subclavian
vein. Lymph nodes in the space between the pectoralis major and minor muscles
are known as the interpectoral group (Rotter‘s nodes). Usually this group are not
encompassed in surgical procedures that preserve the pectoralis group. This should
be compared to the TNM definitions of nodal involvement as discussed later.



Lymphatics
Lymphatic channels are abundant in the breast parenchyma and dermis. Specialized
lymphatic channels collect under the nipple and areola and form Sappey‘s plexus.
Lymph flows from the skin to the subareolar plexus and then into the interlobular
lymphatics of the breast parenchyma. Seventy-five percent of lymphatic flow from
the breast is into the axillary lymph nodes, and the rest goes through the pectoralis
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muscle and into the medial lymph node groups. A major route of breast cancer
metastasis is through lymphatic channels, and the anatomy of the lymphatic system
determines the favoured locations for regional spread of cancer.



Nerve supply
Coursing close to the chest wall on the medial side of the axilla is the long thoracic
nerve (External respiratory nerve of Bell), which innervates the Serratus anterior
muscle. This muscle is important for fixing the scapula to the chest wall during
adduction of the shoulder and extension of the arm. Injury to this nerve results in
the winged scapula deformity. For this reason the long thoracic nerve is preserved
during standard axillary dissection. The second major nerve trunk encountered
during axillary dissection is the thoracodorsal nerve to latissimus dorsi muscle at the
lateral border of the axilla. This nerve arises from the posterior cord of the brachial
plexus and enters the axillary space under the axillary vein, close to the entrance of
the long thoracic nerve. It then crosses the axilla to the medial surface of the
latissimus dorsi muscle. The thoracodorsal nerve is usually preserved during
dissection of the axillary nodes. The medial pectoral nerves innervate the pectoralis
major muscle and are in a neurovascular bundle that wraps around the lateral
border of the pectoralis minor muscle. The pectoral neurovascular bundle is a good
landmark in that it indicates the position of the axillary vein just above and deep
(superior and posterior) to the bundle. This neurovascular bundle needs to be
preserved during standard axillary dissection. The large sensory intercostals brachial
or brachial cutaneous nerves span the axillary space and supply sensation to the
under surface of the upper part of the arm and skin of the chest wall along the
posterior margin of the axilla. Transection of these nerves result in cutaneous
anaesthesia. These nerves can be sacrificed during dissection, but the patient needs
to be informed before hand of the possible side effects.




Relevant pathology

More than a million cases of breast cancer are diagnosed worldwide each year. The
overall incidence of breast cancer has been rising because of increased in the
average life span, lifestyle change that increase risk for breast cancer, and improved
survival from other diseases. Despite an increasing incidence, mortality from breast
cancer has continued to fall, thought to be the result of earlier detection via
mammographic screening and improvements in therapy. Current treatment of
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breast cancer is guided by insights into breast cancer biology, an increasing ability to
define disease biology and status in individual patients, and the availability of
improved treatments



Primary breast cancer can be classified as Non-invasive Epithelial cancers, Invasive
Epithelial cancers and Mixed Connective and Epithelial tumours.



See Table 1 for the Classification of Primary Breast Cancers



Table 1: Classification of Primary Breast Cancers

Non-invasive Epithelial Cancers
Lobular carcinoma in situ (LCIS)
Ductal carcinoma in situ (DCIS)
  Papillary
  Cribiform
  Solid
  Comedo
Invasive Epithelial Cancers (Percentage of Total)
Invasive lobular carcinoma (10-15%)
Invasive ductal carcinoma,
   NOS (50-70%)
   Tubular carcinoma (2-3%)
   Mucinous or colloid carcinoma (2-3%)
   Medullary carcinoma (5%)
   Invasive cribriform carcinoma (1-3%)
   Invasive papillary carcinoma (1-2%)
   Adenoid cystic carcinoma (1%)
   Metaplastic carcinoma (1%)

Mixed Connective and Epithelial Tumors
Phyllodes tumours, benign and malignant
Carcinosarcoma
Angiosarcoma
(Adapted from Sabiston‘s Textbook of Surgery, 18th Edition)



Non-invasive breast cancer can be divided into two major groups, Lobular Carcinoma
In Situ (LCIS) and Ductal Carcinoma In Situ (DCIS). LCIS, once regarded as a
malignant lesion, is now regarded more as a risk factor for the development of
breast cancer, and will not be discussed here.
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Ductal Carcinoma in Situ
DCIS is a more heterogeneous lesion morphologically and four broad categories are
recognised: papillary, cribriform, solid and comedo. DCIS is recognized as discrete
spaces surrounded by basement membrane that are filled with malignant cells and
usually with a recognizable basally located cell layer made up of presumably normal
myoepithelial cells.



The four morphologic categories are protypes of pure lesions, but in reality the types
blend into one another. The papillary and cribriform types probably transform to
invasive cancer over a longer time frame and are of a lower grade. The solid and
comedo types are generally higher-grade lesions and probably invade over a
shortened natural history. As the cells inside the ductal membrane grow they have a
tendency to undergo central necrosis. The necrotic debris in the centre of the duct
undergoes coagulation and finally calcification, thereby leading to the tiny
pleomorphic and frequently linear forms seen on mammograms. In some patients
an entire ductal tree seems to be involved in the malignancy, and the mammogram
shows typical calcifications from the nipple extending posteriorly into the interior of
the breast – the so called segmental calcifications.

An important concept with DCIS is the so called Extensive Intraductal Component
(EIC). The Joint Center for Radiation Therapy defined it as the simultaneous
presence of DCIS comprising 25% or more of the primary invasive tumor and DCIS
in the surrounding normal breast tissue. The definition also includes DCIS with focal
areas of invasion. This is an important concept as will be discussed later, as several
studies have reported an increased risk of recurrence in women with EIC-positive
tumours.

For reasons not understood, DCIS transforms into an invasive cancer, usually
recapitulating the morphology of the cells inside the duct, in other words low-grade
cribriform DCIS tends to invade as a low grade lesions retaining some cribriform
features. DCIS also frequently co-exists with otherwise invasive cancers, and the
two phases of the malignancy are usually in step with each other.



Invasive breast cancer
Invasive cancers are recognized by their lack of overall architecture, by the
infiltration of cells haphazardly into variable amounts of stroma, or by the formation
of sheets of continuous and monotonous cells, without respect for form and function
of a glandular origin. Invasive breast cancer is broadly divided into lobular and
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ductal histology, which probably does not reflect histogenesis. Invasive lobular
cancer tends to permeate the breast in a single-file nature, which explains why it
remains clinically occult and escapes detection on mammography or physical
examination until the total extent is large. Likewise, ductal cancers tend to grow as
a more coherent mass; they form discrete abnormalities on mammograms and
appear sooner as a lump in the breast.



Invasive ductal cancer, also called infiltrating ductal carcinoma is the most common
form of breast cancer and accounts for 50-70% of invasive breast cancers. When
this cancer does not take on special features, it is called Infiltrating ductal
carcinoma, NOS (not otherwise specified). Invasive lobular carcinoma accounts for
10-15% of breast cancers, and mixed ductal and lobular cancers are increasingly
being recognised. When ductal carcinomas take on differentiated features they are
named according to the features that they display. If the infiltrating cells secrete
copious amounts of mucinous material they are called mucinous carcinomas.
Tubular and mucinous tumours are low grade lesions and each represent about 2-
3% of invasive ductal carcinomas.



Grading of breast cancer: Histological Grade (G)
All invasive breast carcinomas should be graded. The Nottingham combined
histologic grade (Elston-Ellis modification of Scarff–Bloom–Richardson grading
system) is recommended by the AJCC. The grade for a tumor is determined by
assessing morphologic features (tubule formation, nuclear pleomorphism, and
mitotic count), assigning a value of 1 (favourable) to 3(unfavourable) for each
feature, and adding together the scores for all three categories. A combined score of
3–5 points is designated as grade 1; a combined score of 6–7 points is grade 2; a
combined score of 8–9 points is grade 3.



HISTOLOGIC GRADE         (NOTTINGHAM       COMBINED      HISTOLOGIC      GRADE     IS
RECOMMENDED)

GX Grade cannot be assessed

G1 Low combined histologic grade (favourable)

G2 Intermediate combined histologic grade (moderately favourable)

G3 High combined histologic grade (unfavourable)
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Staging of breast cancer


Breast cancer stage is determined by the results of surgical resection and imaging
studies. Breast cancer is classified with the TNM classification system. The most
widely used system is that of the American Joint Committee on Cancer (AJCC). This
system is based on the description of the primary tumour (T), the status of the
regional lymph nodes (N) and the presence of distant metastases (M).



This staging system for carcinoma of the breast applies to invasive (also designated
infiltrating) as well as in situ carcinomas, with or without micro invasion. Microscopic
confirmation of the diagnosis is mandatory, and the histologic type and grade of
carcinoma should be recorded. For all sites (T, N, M), clinical staging (c) is
determined using information identified prior to surgery or neoadjuvant therapy.
Pathologic staging (p) includes information defined at surgery. With neoadjuvant
therapy a post therapy pathologic staging is recorded using the ―yp‖ designator.



Table 2 -5 represents the most recent AJCC Cancer staging system for Breast cancer
as updated in 2010.



Table 2: TNM Staging: Primary Tumor (T)
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Table 3: TNM Staging: Regional Lymph Nodes (N)
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Table 4: TNM Staging: Distant Metastases (M)




Table 5: TNM Staging: ANATOMIC STAGE/PROGNOSTIC GROUPS
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Modern classification schemes are replacing the older morphological descriptions
with the determination of molecular markers, Estrogen receptors, Progesterone
receptors and HER-2 cell surface receptors

If all three of the above receptors are absent on the tumour, the tumours are
sometimes referred to as triple-negative breast cancers.




Relevant oncology
Anatomy and the influence thereof on cancer spread and
metastases
Primary Site
The mammary gland, situated on the anterior chest wall, is composed of glandular
tissue with a dense fibrous stroma. The glandular tissue consists of lobules that
group together into 8–15 lobes, occasionally more, arranged approximately in a
spoke-like pattern. Multiple major and minor ducts connect the milk-secreting lobular
units to the nipple. Small milk ducts course throughout the breast, converging into
larger collecting ducts that open into the lactiferous sinus at the base of the nipple.
Each duct system has unique anatomy: the smallest systems may comprise only a
portion of a quadrant whereas the largest systems may comprise more than a
quadrant. The periphery of each system overlaps along their radial boundaries. Most
cancers form initially in the terminal duct lobular units of the breast. Carcinoma
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spreads along the duct system in the radial axis of the lobe; invasive carcinoma is
more likely to spread in a centripetal orientation in the breast stroma from the initial
locus of invasion, although opportunistic intraductal spread may be enhanced along
the radial axes. Glandular tissue is more abundant in the upper outer portion of the
breast; as a result, half of all breast cancers occur in this area.

Chest Wall
The chest wall includes ribs, intercostal muscles, and serratus anterior muscle, but
not the pectoral muscles. Therefore, involvement of the pectoral muscle does not
constitute chest wall invasion.

Regional Lymph Nodes
The breast lymphatics drain by way of three major routes: axillary, transpectoral,
and internal mammary. Intramammary lymph nodes reside within breast tissue and
are coded as axillary lymph nodes for staging purposes. Supraclavicular lymph nodes
are classified as regional lymph nodes for staging purposes. Metastases to any other
lymph node, including cervical or contra lateral internal mammary or axillary lymph
nodes, are classified as distant (M1)

The regional lymph nodes are as follows:

1. Axillary (ipsilateral): interpectoral (Rotter‘s) nodes and lymph nodes along the
axillary vein and its tributaries that may be (but are not required to be) divided into
the following levels:

a. Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor
muscle.

b. Level II (mid-axilla): lymph nodes between the medial and lateral borders of the
pectoralis minor muscle and the interpectoral (Rotter‘s) lymph nodes.

c. Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis
minor muscle and inferior to the clavicle. These are also known as apical or
infraclavicular nodes. Metastases to these nodes portend a worse prognosis.
Therefore, the infraclavicular designation will be used hereafter to differentiate these
nodes from the remaining (level I, II) axillary nodes.

2. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the
edge of the sternum in the endothoracic fascia.

3. Supraclavicular: lymph nodes in the supraclavicular fossa, a triangle defined by
the omohyoid muscle and tendon (lateral and superior border), the internal jugular
vein (medial border), and the clavicle and subclavian vein (lower border). Adjacent
lymph nodes outside of this triangle are considered to be lower cervical nodes (M1).
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4. Intramammary: lymph nodes within the breast; these are considered axillary
lymph nodes for purposes of N classification and staging.

Metastatic Sites
Tumor cells may be disseminated by either the lymphatic or the blood vascular
system. The four major sites of involvement are bone, lung, brain, and liver, but
tumor cells are also capable of metastasizing to many other sites.

Bone marrow micro metastases, circulating tumor cells, and tumor deposits no larger
than 0.2 mm detected inadvertently, such as in prophylactically removed ovarian
tissue, are collectively known as microscopic disseminated tumor cells (DTCs).

These deposits do not alone define or constitute metastatic disease, although there
are data that demonstrate that, in early stage disease, DTCs correlate with
recurrence and mortality risk, and in patients with established M1 disease, circulating
tumor cells (CTCs) are prognostic for shorter survival.




Schematic of the breast and regional lymph nodes
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Ipsilateral breast tumor recurrence
In their seminal work on the local therapy of breast cancer, Fisher et al. popularized
the term ‗‗in-breast tumor recurrence‘‘ or ipsilateral breast tumor recurrence (IBTR).
This has become common parlance in studies of breast preserving therapy, and is a
reasonable pragmatic concept, given the difficulties of distinguishing true local
recurrences from new primary tumors of the breast, particularly in the setting of
large multicenter trials.

However, it is also important to recognize that there are distinct patterns of survival
related to a true local recurrence versus the new ipsilateral breast primaries with
which they have so far been grouped. The major difference is a longer interval to
occurrence and better overall prognosis. Another aspect of the definition of IBTR is
that it includes recurrences in the skin of the breast; these can occur following
breast conservation or mastectomy, and in general imply a poorer prognosis than
pure parenchymal recurrences in the conserved breast.

Finally, it should be noted that the definition of local recurrence used by the EBCTG
includes both inbreast and loco-regional recurrences, but results from the pooled
analysis of the NSABP trials show that in-breast recurrences have a far smaller
prognostic disadvantage than other loco-regional recurrences, which are mainly
nodal. Similar findings are reported from the large database of the Milan Institute of
Oncology. These distinct effects on outcomes point to the need for clear distinction
between the types of local and regional disease that can follow breast cancer
therapy, and the specific treatment modalities that can minimize the risk of
recurrence.




Clinical Trials

Before discussing the place of breast conserving surgery it is useful to give an
overview of the evidence base upon which the current recommendations of
treatment are founded, as the discussion regarding breast conserving surgery will
frequently reference one of these studies. Firstly, I will briefly highlight the landmark
studies by the National Surgical Adjuvant Breast Project (NSABP). Only the
essentials will be listed, but for further reading there is an excellent article published
in the Surgical Clinics of North America 2007. Secondly, I will endeavour to highlight
the landmark trials (level 1A evidence) which changed standards of practice, and
give a brief explanation of the rationale behind each trial, what it involved, and a
summary of the results. The reader will notice that some of the NSABP trials are
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included in this discussion, and the perceived replication serves to highlight the
importance of said trials. Lastly a brief summary will be given of some of the non
randomized or single centre trials that delivered answers to some of the outstanding
questions, or which strengthened the current evidence based recommendations.



Review of Breast Cancer Clinical Trials Conducted by the National
Surgical Adjuvant Breast Project Adapted from the Surgical Clinics of North
America 87 (2007) 279–305


The National Surgical Adjuvant Breast Project (NSABP) is a National Cancer Institute
(NCI)-funded clinical trials cooperative group that for the past 51 years has
conducted multiple randomized clinical trials on the loco-regional and adjuvant
systemic therapy of early-stage breast cancer, as well as on breast cancer
chemoprevention. Results from many of these trials have undoubtedly been
responsible for defining new standards of breast cancer care worldwide. What
follows is a summary of the design, primary aims, and main results from selected
NSABP trials evaluating loco-regional and adjuvant systemic therapy questions.

National Surgical Adjuvant Breast Project B-04
The National Surgical Adjuvant Breast Project B-04 set out to design a large
prospective randomized clinical trial to examine whether reducing the extent of
surgery for breast cancer might not compromise outcome. The NSABP B-04 trial was
set up as two companion trials conducted in parallel: one trial for patients who had
clinically node-negative breast cancer and the other for patients who had clinically
node-positive disease. Because the Radical Mastectomy (RM) was the standard-of-
care management at that time, this operation was included as the control arm for
both trials there were no significant differences in overall survival among the three
arms in the clinically node-negative patients, even with 25 years of follow- up: 25%
for the RM arm; 19% for the TM/radiation arm; and 26% for the TM-alone arm.
Similarly, there were no overall survival differences between the two arms in the
clinically node-positive patients (overall survival: 14% for each arm).

National Surgical Adjuvant Breast Project B-06
The B-06 trial was designed for women who had operable primary breast cancer no
larger than 4 cm in greatest diameter. Between 1976 and 1984, 2163 patients were
randomized to one of three different treatment arms: (1) modified radical
mastectomy (MRM) the standard of care referent group; (2) lumpectomy, ALND, and
breast radiation; or (3) lumpectomy and ALND. After 20 years of follow-up, there
continue to be no significant differences in overall survival, disease-free survival, or
                                                                            P a g e | 20


distant disease-free survival between the group of patients who underwent MRM and
the groups treated with lumpectomy with or without breast radiation. The hazard
ratios for death comparing the lumpectomy-alone and lumpectomy-plus-radiation
arms to the mastectomy arm were 1.05 (95% CI, 0.90–1.23) and 0.97 (95% CI,
0.83–1.14), respectively. Despite lack of significant differences in overall survival,
significant differences in local control of the disease were observed among the three
arms of the B-06 trial. In-breast recurrence occurred in 39.2% of the patients
randomized to lumpectomy alone, compared with 14.3% in those randomized to
lumpectomy plus breast irradiation. Chest wall recurrence was observed in 10.2% of
the patients in the mastectomy arm. Nearly three quarters of the local recurrences in
the lumpectomy-alone arm occurred within the first 5 years after surgery, compared
with the lumpectomy and irradiation arm, in which 40% of recurrences occurred
within the first 5 years.

Thus the NSABP B-06 trial established the safety of breast-conserving surgery for
early-stage invasive breast cancer, and demonstrated the importance of adjuvant
breast radiation to minimize risk of in-breast recurrence. Furthermore, along with
other randomized trials including those conducted by the Milan group evaluating
quadrantectomy the B-06 trial was instrumental in establishing breast-conserving
surgery plus radiotherapy as the preferred method of local treatment for patients
who have operable breast cancer.



National Surgical Adjuvant Breast Project B-21
One of the unresolved questions following disclosure of the results from the B-06
trial, as well as those from the Milan trial, was whether all patients who had invasive
breast cancer undergoing lumpectomy needed postoperative radiotherapy. Women
who had node-negative invasive breast cancer 1 cm or less in diameter treated with
lumpectomy and axillary dissection were randomized tamoxifen alone for 5 years,
breast radiation plus tamoxifen for 5 years, or breast radiation plus placebo for 5
years.

Published results demonstrated that radiation and placebo resulted in a 49% lower
hazard rate of in-breast recurrence than did tamoxifen alone; radiation and
tamoxifen resulted in a 63% lower rate of in-breast recurrence than did radiation
and placebo. When compared with tamoxifen alone, radiation and tamoxifen
resulted in an 81% reduction in hazard rate of inbreast recurrence. Cumulative
incidence of in-breast recurrence through 8 years was 16.5% with tamoxifen alone,
9.3% with radiation and placebo, and 2.8% with radiation and tamoxifen. Radiation
reduced in-breast recurrence below the level achieved with tamoxifen alone,
regardless of estrogen receptor status. Survival in the three groups was 93%, 94%,
                                                                            P a g e | 21


and 93%, respectively (P ¼ .93). Thus, this trial demonstrated that in the group of
node-negative patients who had small invasive tumors treated by lumpectomy,
tamoxifen was not as effective as breast radiation in controlling the disease in the
breast. It further demonstrated that the combination of tamoxifen and breast
radiation results in better local control of the disease in the breast than either
modality alone.

National Surgical Adjuvant Breast Project B-17
As randomized trials demonstrated the value of breast-conserving surgery in patients
who have invasive breast cancer, an obvious question arose relative to the value of
this procedure in patients who have non-invasive disease. Based on the results of
the B-06 and other trials described above, in the early 1980s there was a paradox in
the surgical treatment of early-stage breast cancer, with invasive disease being
treated progressively more with lumpectomy, whereas mastectomy remained the
recommended surgical treatment for non-invasive disease. Thus, it became
imperative at the time to test the value of breast conservation in patients who have
DCIS. The NSABP was the first group to conduct such a prospective randomized
trial.

The NSABP B-17 trial compared lumpectomy alone with lumpectomy plus breast
radiation in 818 patients who had localized ductal carcinoma in-situ. A mastectomy
control group was not included, given the acceptance of lumpectomy based on the
results of the B-06 trial, as well as the excellent prognosis of patients who had
localized DCIS. Recently updated results from the B-17 trial after 12 years of follow-
up continue to indicate as previously reported that radiotherapy significantly
decreases the rate of invasive and non-invasive ipsilateral breast tumor recurrence.
The cumulative incidence of non-invasive ipsilateral breast cancer recurrence as a
first event was significantly reduced with breast radiation from 14.6% to 8.0% (P ¼
.001).

More importantly, the cumulative incidence of invasive ipsilateral recurrence was
also significantly reduced from, 16.8% to 7.7% (P ¼ .00001). No difference in
overall survival has been observed between the two groups (86% versus 87%, P ¼
.80), and over two thirds of the deaths occurring in this trial were not breast-cancer
related. In a subset of 623 out of 814 evaluable patients from this trial, pathologic
features were analyzed relative to their prognostic significance for ipsilateral breast
cancer recurrence. Only the presence of moderate/ marked comedo necrosis was a
statistically significant independent predictor of risk for ipsilateral breast cancer
recurrence in both treatment groups, and breast radiation markedly reduced the
annual hazard rates for ipsilateral breast cancer recurrence in all subgroups of
patients
                                                                           P a g e | 22


Thus the current evidence from the above trials can be summarized as follows:

NSABP B-04: Overall survival independent of node status is the same for Radical
Mastectomy vs. Modified radical mastectomy with Radiation

NSABP B-06: There are no significant differences in overall survival, disease-free
survival, or distant disease-free survival between Modified radical mastectomy,
lumpectomy, axillary dissection and breast radiation.

NSABP B-21: Node negative small breast carcinomas treated with BCS had lower
recurrence with radiation therapy, than with chemotherapy. The combination of
radiation therapy and chemotherapy yielded the lowest recurrence rates.

NSABP B-17: Radiotherapy significantly decreases the rate of invasive and non-
invasive IBTR in DCIS treated with BCS.

The sheer number of breast cancer-related randomized, controlled trials makes it
impossible to review all level IA evidence in this review, but a few landmark trials
that are relevant to the topic are highlighted.



LEVEL IA EVIDENCE: PROSPECTIVE RANDOMIZED SURGICAL
TRIALS IN BREAST CANCER
1. Twenty-five-year follow-up of a randomized trial comparing radical
mastectomy, total mastectomy, and total mastectomy followed by
irradiation. Fisher B, Jeong JH, Anderson S, et al. N Engl J Med 2002; 347:567–
75.1

The NSABP B-04 trial compared less extensive operations (TM) with or without RT to
traditional RM in women with primary operable breast cancer, and with long-term
follow-up, no differences in any survival outcomes were observed. NSABP B-04 has
been fundamental in shaping the approach to breast cancer treatment for the last 35
years as its findings supported the ‗‗systemic‘‘ disease hypothesis, which proposed
that alterations in local therapy were unlikely to impact survival. The proof of
principle that more radical treatment did not increase cure rate opened the door for
subsequent trials of BCT. Of note, 40% of the clinically node-negative patients in the
RM arm of NSABP B-04 had nodal involvement on final pathology, but only 18% of
those in the no axillary lymph node dissection (ALND) arm developed clinical axillary
recurrence requiring delayed ALND.

This result, coupled with the lack of survival differences observed between arms, led
to ALND being regarded as a staging rather than a therapeutic procedure. For this
reason, the role of completion dissection after a positive sentinel node biopsy (SLNB)
                                                                            P a g e | 23


is a source of debate, but when considering the role of B04 in defining appropriate
treatment of the axilla, it is important to recall that no systemic therapy was used in
the trial, and by modern standards B04 was underpowered to detect a small (less
than 10%) benefit in survival related to ALND



2. Twenty-year follow-up of a randomized trial comparing total
mastectomy, lumpectomy, and lumpectomy plus irradiation for the
treatment of invasive breast cancer. Fisher B, Anderson S, Bryant J, et al. N Engl
J Med 2002;347:1233–41.2

Hypothesis: BCT with RT is equivalent to TM

NSABP-06 was designed to evaluate the efficacy of BCT with and without RT in
women with tumors smaller than 4 cm in diameter. The trial is one of several large
studies evaluating the role of BCT and now reporting follow-up at 13 to 20 years
after randomization. The findings reported here are similar to those previously
published; no differences in survival exist between the treatment groups. The use of
adjuvant RT did significantly reduce IBTR in both node-positive and node-negative
patients undergoing lumpectomy, and recurrence in patients treated without RT
occurred earlier (73% within 5 years of surgery) than in those treated with RT (40%
within 5 years of surgery).

In comparing NSABP B-06 to the Milan, EORTC 10801, and National Cancer Institute
(NCI) trials, it is important to realize that excision to negative margins was not
required for the NCI and EORTC 10801 studies, resulting in higher rates of IBTR,
and confirming that complete surgical resection with negative (no tumor on ink)
margins is an essential component of BCT. In NSABP B-06, only patients with
positive axillary nodes received adjuvant chemotherapy. This treatment combined
with RT resulted in 50% fewer IBTRs (8.8%) than seen with RT alone in the lower
risk node-negative patients (17%), indicating that chemotherapy can act
synergistically with RT to prevent a subset of local recurrences.



3. Effects of radiotherapy and of differences in the extent of surgery for
early breast cancer on local recurrence and 15-year survival: an overview
of the randomised trials. Early Breast Cancer Trialists‘ Collaborative Group
(EBCTG). Lancet 2006;366:2087–106.6

The Early Breast Cancer Trialists‘ Collaborative Group (EBCTG) has centrally
reviewed individual patient data every 5 years since 1985 to study the effects of RT
and the extent of surgery on local control and cause-specific mortality in early breast
                                                                             P a g e | 24


cancer. An important new finding in the 15-year review is that differences in local
recurrence of greater than 10% at 5 years result in statistically significant
differences in OS at 15 years. The ratio of absolute effect is 4 to 1 (i.e., for every 4
local recurrences prevented, 1 life is saved). This principle is reflected in analyses
addressing lumpectomy with or without RT, an adjuvant therapy resulting in an
absolute risk reduction (ARR) of 19% in IBTR and 5.4% in breast cancer–specific
mortality in this meta-analysis. Node-positive mastectomy patients similarly
experienced large risk reductions in 5-year local recurrence with adjuvant RT (23%
vs. 6%), translating into a 15-year ARR in breast cancer–specific mortality of 5.4%.

Survival outcomes in node-negative patients treated with modified radical
mastectomy (MRM) were not improved with RT, a reflection of the small difference
in local control between groups (ARR 4%). Subgroup analyses did not identify BCT
patients who failed to benefit from adjuvant RT. Another finding of the meta-analysis
was that adjuvant RT results in a small increase in long-term mortality related to
contralateral breast cancer, heart disease, and lung cancer. The increase in these
events was 1.3% at 15 years and did not exceed the benefit of RT on breast cancer-
specific survival. The impact of modern chemotherapy and RT regimens on these
outcomes requires further study



Other trials
The Milan I trial showed a survival benefit that was not statistically significant in
axillary node–positive patients treated with quadrantectomy and radiotherapy
compared with radical mastectomy.

A meta analysis reported by the Early Breast Cancer Trialists‘ Collaborative Group
(EBCTCG) comparing BCS versus BCS and radiation therapy demonstrated that the
addition of radiation therapy after BCS reduced the risk of local recurrence from
32% at 10 years to 10.3%, respectively, and resulted in a 15-year gain of about
5%-5.5% in both breast cancer mortality and overall mortality. Similarly, there was
a decrease in the 15-year risk of dying from breast cancer from 31% to 26% in
patients with node-negative disease and 55%-48% in patients with node-positive
disease.

The Early Breast Cancer Trialists‘ Collaborative Group overview indicates that as a
rule of thumb, every 4 local recurrences avoided by RT prevents 1 death 15 years
after diagnosis. Therefore, RT is expected to improve survival in subgroups where
the absolute risk reduction for local recurrence is 10%. This group includes the
majority of women with invasive breast cancer treated with breast-conserving
surgery
                                                                           P a g e | 25




Choosing what type of surgery to do
The major issue for surgical therapy, for both surgeon and patient, remains the
decision regarding breast conserving therapy versus mastectomy. This decision
hinges on the assessment of the risk of inbreast recurrence following breast
conservation, and the principle that breast conservation should not be pursued if the
risk of in-breast recurrence is high.

There are a few contraindications to Surgery as the initial therapy for Breast cancer,
irrespective of choice of mastectomy or BCS, these are listed in Table 6.



TABLE 6 Contraindications to Surgery as the Initial Therapy for Breast
Cancer




There are clearly identifiable subsets where the risk of inbreast recurrence exceeds
10% threshold that can be considered tolerable for the safe use of breast conserving
therapy. However, in counselling patients about optimal surgical therapy, it is
important to note that local recurrence is also possible following mastectomy; the
EBCTG overview points out that even in node-negative tumors, the rate of post-
                                                                             P a g e | 26


mastectomy recurrence hovers around 5%. A consideration of the risk factors for
post-mastectomy versus post-BCT local recurrence is therefore worthwhile. The
strongest risk factors for post-mastectomy local recurrence is acknowledged to be
nodal involvement; this is addressed by appropriate use of RT and systemic therapy,
and surgical decision-making is relevant only to the extent of providing thorough
axillary clearance. Following breast conservation, the strongest risk factors for local
recurrence are a failure to use RT, and the presence of positive resection margins. A
number of additional risk factors for in-breast recurrence have been identified, and
in making recommendation regarding optimal surgical therapy, it is important to
identify those that are unique to recurrence in the conserved breast, discussed
below.

A second tier of risk factors includes the presence of lymphovascular invasion, and
tumor grade, the histological tumor type (i.e., ductal vs. lobular), tumor size, and
family history of breast cancer (with or without BRCA mutations). These have not
proven to be reproducible, independent risk factors for local recurrence following
breast conservation, and therefore should not be the basis of decisions for
mastectomy.



Mastectomy as best choice
Present firm indications for mastectomy include: (1) inability to deliver breast RT; (2)
multicentric disease; and (3) inability to achieve clear margins following more than
one attempt at breast conservation. In all of these areas, new developments are
leading to re-examination of the need for mastectomy. On the other hand, the
uniformity of the data establishing young age (<40 years) as a risk factor for local
recurrence is raising questions as to whether youth should be a selection factor for
mastectomy. Finally, recent information about the risk of loco-regional recurrence in
the various molecularly defined subtypes of breast cancer has raised the question of
selection of surgical therapy based on biologic subtype.

Inability to deliver breast radiotherapy
 The use of whole breast radiation therapy reduces the risk of in-breast recurrence
by approximately two-thirds, and although analyses of individual trials did not show
a significant survival benefit with the use of RT, the EBCTG analysis discussed
above, and the resulting recognition that the use of RT confers a survival advantage,
means that breast conservation should not be offered without the ability to follow
surgery with radiation. Therefore, even subsets of patients for whom RT was
previously considered optional (e.g., the over 70 age group) should be counselled
about this potential benefit when making a breast conservation decision. Patients
                                                                             P a g e | 27


who have had prior breast RT (i.e., mantle radiation for Hodgkin‘s lymphoma), are
presently not considered candidates for breast conservation, although it is possible
that the advent of partial breast RT will temper these recommendations. A scenario
where the omission of breast RT comes up regularly is the patient with an in-breast
recurrence or new primary tumor in a conserved (and radiated) breast.

The use of repeat breast conservation in this situation is controversial, since it is
associated with 5-year local recurrence rates of 20% in larger series. However, it can
be argued that the rate of distant events tends to be higher than that of second
local failure, and it is this that defines overall survival (OS). Retrospective data on
repeat breast conserving surgery from the Milan Institute of Oncology included a
highly selected group of 161 of 288 (56%) women with isolated local recurrence.

The remainder were treated with mastectomy. Repeat breast conservation was
accompanied by a local recurrence risk of 21% at 5 years, but in a subset of patients
with small (<2 cm) recurrences, a lengthy disease-free interval (>4 years), and
favourable biology (hormone receptor positive, low proliferation index, HER-2
negative), local recurrence risk was 12.8%. The investigators suggest that repeat
BCT may be feasible in this highly selected group, and is unlikely to reduce survival.

A population-based study on this issue reaches quite different results; in a search of
the Surveillance Epidemiology and End Results (SEER) database of the National
Cancer Institute (NCI), 747 women with isolated local recurrence following BCT were
identified. Approximately 20% of them received repeat BCT. Analysis of OS by
surgical treatment group revealed a significant survival disadvantage to the repeat
BCT group (67% vs. 78% at 5 years). Although this analysis suffers from the usual
limitations of large, population-based registries (i.e., missing data, lack of detail on
surgical margins and systemic therapy), the magnitude of the effect is striking, and
should give pause to considerations of repeat breast conservation.

The data discussed above do not include re-radiation of the breast, the feasibility of
which has been reported in several small series. However, when a tumor has
demonstrated some level of radiation resistance by re-appearing despite the use of
RT, it remains questionable whether further RT will achieve the same benefit as
mastectomy. As discussed above, new primaries have distinctly better outcomes,
and when the new tumor is small and hormone receptor positive, particularly when
the interval from the index tumor is long, it is tempting to explore the possibility of
repeat breast conservation. However, since no favourable subsets have been
identified in the setting of primary disease that will allow the avoidance of breast
irradiation, it is unlikely that such subsets exist for secondary tumors. Future
validation of partial breast RT may allow this issue to be revisited.
                                                                            P a g e | 28




Multicentric disease
Several older retrospective studies suggested that the risk of in-breast recurrence
following breast conservation for multicentric disease was unacceptably high, in the
range of 25–40%. However, many of these earlier studies did not reach uniform
standards in terms of the use of RT or of margin assessment. Contemporary
investigations into the frequency of inbreast recurrence following breast
conservation in the setting of multicentric disease suggest that local control
equivalent to that seen with unifocal disease can be achieved with careful attention
to current standards of care.

Where comparisons between mastectomy and breast conservation are possible, the
use of mastectomy does not seem to confer advantages in terms of local control or
survival. These data are limited by small numbers and retrospective analyses, but
deserve attention and suggest the need for well-designed prospective studies,
especially since multicentric disease is an increasingly frequent finding with the
advent of magnetic resonance imaging (MRI) of the breast, and the biologic
importance of such multicentric disease is unknown.

However, even if breast conservation is safe in women with multicentric disease, the
volume of resection required and the need to adhere to high local therapy standards
(e.g., free resection margins, the use of boost RT, particularly in young women) may
limit the practical application of breast conservation in the presence of multicentric
breast cancer.

Inability to achieve clear margins
Successful breast conserving surgery requires margins clear of invasive and ductal
carcinoma in situ (DCIS), achieved with acceptable cosmetic results. The original
definition of free resection margins used by the NSABP in the B-06 trial, and all
subsequent NSABP trials, was the stipulation that there should be no ink on the
tumor cells. Local control rates of 95% at 10 years are reported in patients receiving
systemic therapy when this definition is used.

Since then, a number of investigators have examined the benefit of wider resection
margins, generally in single institution retrospective analyses, with variable findings
regarding improved control. Although there is conclusive evidence linking higher
rates of IBTR to the presence of positive margins, there is no consistent evidence
that widely free margins lead to fewer local recurrences. Although not reported, it
seems likely that higher mastectomy rates are a similar consequence, along with a
higher psychological and financial burden.
                                                                              P a g e | 29


Nevertheless, wider margins may be considered for patients younger than 40 years,
and situations where margin assessment is challenging (e.g., tumors with an
extensive intraductal component or diffuse growth pattern, or after neoadjuvant
chemotherapy). The impact of focally (i.e., <1 histological field at 4x magnification)
involved margins on the risk of local relapse appears to be small, and in the
presence of other favourable features such as older age, focally positive margins
may be tolerated. Lobular carcinoma in situ at the margin is not considered an
indication for further surgery.

Most publications reporting on the impact of margin positivity on local recurrence
risk have not distinguished between the presence of invasive carcinoma and DCIS at
the margin; when excisions are being performed for pure DCIS, a recent meta-
analysis suggests that there is an advantage to increasing margin width up to 2 mm,
but margins >2mm were not associated with any further reduction in local
recurrence risk.

Age
A large number of studies have established young age as a risk factor for loco-
regional recurrence. These findings are summarized in results from the EBCTG,
where young age was a significant risk factor for local recurrence after breast
conserving surgery plus RT. This raises the question of whether young women who
opt for BCT may be increasing the hazard of death since their local recurrence risk is
approximately twofold higher than that of older women. However, it is of interest
that the risk of local recurrence following mastectomy plus RT in the EBCTG analysis
was not age-dependant. Recalling that the EBCTG definition of local recurrence
included all types of loco-regional recurrence, this would suggest that the higher risk
for young women following BCT is specifically for in-breast recurrence, and not for
regional nodal recurrence. Since it is these regional recurrences—the so-called other
loco-regional recurrences (oLRR) in the NSABP pooled analyses—that have the
greater impact on survival, one can surmise that the use of BCT in appropriately
selected young women, with adherence to the standards of tumor-free margins and
boost RT, will not jeopardize survival, since the only risk that is unique to BCT is that
of true intraparenchymal recurrence. However, further analyses that distinguish
between these specific subtypes of loco-regional recurrence and its impact on
survival are required.

Biologic subtypes of breast cancer
Over the past decade, studies of molecular profiling of breast cancer have led to the
delineation of four biologic subtypes of breast cancer: luminal A (hormone receptor
positive and HER-2 negative); luminal B (hormone receptor positive and HER-2
positive); HER-2 positive; and hormone receptor negative and triple negative. This
                                                                             P a g e | 30


delineation of subtypes has profound prognostic and therapeutic implications.
Several investigators have recently examined the impact of biologic subtypes of
breast cancer on local control, with generally similar, though not unanimous, results.
Studies which include patients treated in more remote time periods tend to show
little difference in local recurrence rates across biologic subtypes, but a large recent
analysis which included patients treated in the time period 1998–2001 revealed a
significantly higher adjusted hazard of local recurrence in luminal B and basal-like
tumors.

However, as pointed out by Nguyen et al., the local recurrence risk of luminal A
tumors in older studies is substantially higher than that of contemporary series,
suggesting that the changes in local management that have occurred in recent years
(e.g., imaging, margin evaluation, radiation boost) have greatly improved local
control success in more indolent tumors, but that the more aggressive biologic
tumor types are resistant to these manoeuvres.

It is noteworthy that even in the aggressive subtypes, the 10-year local recurrence
rates in recently treated patients under 10%. Also of interest is the fact that with
biologic subtype included in the multivariate analysis, age was no longer a significant
predictor of local recurrence risk. Finally, although differences by biologic subtype
with regard to local recurrence were significant, the impact on OS was far more
dramatic, reminding us that the loco-regional events are a reflection of overall
disease behaviour, and that treatment with mastectomy is unlikely to change the
ultimate course of the disease.




Breast conserving surgery
Between 1980 and 2004, the mastectomy rate at the Mayo Clinic fell from 91% to
36%, 13 and currently about 66% of women with early breast cancer will have BCS

A spectrum of surgical procedures has been employed in BCT. These include
quadrantectomy, segmentectomy, partial breast resection, wide excision,
lumpectomy, and tylectomy. The procedures are similar in that the majority of
breast tissue is preserved, but they differ in rationale and how much normal tissue is
removed along with the tumor. Many surgeons believe the surgical procedure for
BCT is more difficult to perform than mastectomy because each case differs and
requires judgment regarding the extent of normal tissue that should be removed to
both minimize subclinical disease but also preserve the cosmetic result.

Four critical elements in patient selection for breast conservation treatment are
history and physical examination, mammographic evaluation, histologic assessment
                                                                           P a g e | 31


of the resected breast specimen, and assessment of the patient‘s needs and
expectations.

History and physical examination
Much of the information needed to determine a patient‘s suitability for breast
conservation therapy can be obtained from a detailed history and physical
examination. Age per se, whether young or old, is not a contraindication to breast
conservation. In the elderly, physiologic age and the presence of comorbid
conditions should be the primary determinants of local therapy. The elements of the
breast history and physical examination are listed in Tables 8 and 9. Retractions of
skin, nipple, and breast parenchyma are not signs of locally advanced breast cancer
and are not contraindications to breast conservation.



Mammographic evaluation
Recent preoperative mammographic evaluation is necessary to determine a patient‘s
eligibility for breast conservation treatment. It should be done with high quality,
dedicated mammographic equipment (usually within 3 months) mammographic
evaluation, before biopsy or definitive surgery, plays an important role in
establishing the appropriateness of breast-conservation treatment.

Mammographic evaluation defines the extent of a patient‘s disease, the presence or
absence of multicentricity, and other factors that might influence the treatment
decision and evaluates the contra lateral breast. Bilateral mammography is needed
for palpable lesions and nonpalpable lesions that can be identified only
radiographically. An increasing percentage of carcinomas treated with breast
conservation are nonpalpable masses and microcalcifications.

The breast tumor should be measured in at least two dimensions on the
mammographic views or from the sonogram during ultrasonography, if it is
performed. The size of the tumor should be included in the mammographic report. If
the tumor is a poorly marginated mass, approximate dimensions can be given from
either the mammogram or the sonogram. The skin of the breast in the area of a
mass should be evaluated for thickening that might signify tumor involvement. If the
mass is associated with microcalcifications, an assessment of the extent of the
calcifications within and outside the mass should be made. Dimensions of the area in
which calcifications are located should be given. If one or more clusters of
microcalcifications are the only markers of the tumor, their location and distribution
should be described.
                                                                          P a g e | 32


For evaluation of masses and microcalcifications, specialized views with positioning
adapted to the location of the abnormality may be helpful. Magnification
mammography and spot compression are important for characterizing
microcalcifications and defining the margins of masses. Ipsilateral multifocality or
multicentricity may be present and influence the treatment selection. In every
instance, when one abnormality is seen, all areas of each breast should be fully
evaluated for the presence of additional disease.

Pathological features influencing treatment choice
Numerous pathologic factors have been assessed for their ability to predict an
increased risk of recurrence in the treated breast in patients undergoing
conservative surgery and radiation. Following breast conservation, the strongest risk
factors for local recurrence are a failure to use RT, and the presence of positive
resection margins. A number of additional risk factors for in-breast recurrence have
been identified, and in making recommendation regarding optimal surgical therapy,
it is important to identify those that are unique to recurrence in the conserved
breast, discussed below.

A second tier of risk factors includes the presence of lymphovascular invasion, and
tumor grade, the histological tumor type (i.e., ductal vs. lobular), tumor size, and
family history of breast cancer (with or without BRCA mutations). These have not
proven to be reproducible, independent risk factors for local recurrence following
breast conservation, and therefore should not be the basis of decisions for
mastectomy.



Patient preferences
Perhaps the most difficult aspect of patient evaluation is the assessment of the
patient‘s needs and expectations regarding breast preservation. The patient and her
physician must discuss the benefits and risks of mastectomy compared with those of
breast-conservation treatment in her individual case with thoughtful consideration of
each. Each woman must evaluate how her choice of treatment is likely to affect her
sense of disease control, self-esteem, sexuality, physical functioning, and overall
quality of life. The following factors should be considered:

1. Long-term survival

2. The possibility and consequences of local recurrence

3. Psychological adjustment (including the fear of cancer recurrence), cosmetic
outcome, sexual adaptation, and functional competence
                                                                           P a g e | 33


For most patients, the choice of mastectomy with or without reconstruction or
breast-conservation treatment does not influence the likelihood of survival, but it
may affect the quality of life.

Psychological research comparing patient adaptation after mastectomy with that
after breast conservation treatment shows no significant differences in global
measures of emotional distress. Research also does not reveal significant changes in
sexual behaviour and erotic feelings in the treated breast or nipple and areolar
complex. However, women whose breasts are preserved have more positive
attitudes about their body image and experience fewer changes in their frequency of
breast stimulation and feelings of sexual desirability.



Absolute and relative contraindications
Some absolute and relative contraindications exist in the selection of patients for
breast conservation treatment with radiation.

Absolute Contraindications
Pregnancy is an absolute contraindication to the use of breast irradiation. However,
in many cases, it may be possible to perform breast-conserving surgery in the third
trimester and treat the patient with irradiation after delivery. Women with two or
more primary tumors in separate quadrants of the breast or with diffuse malignant-
appearing microcalcifications are not considered candidates for breast-conservation
treatment.

A history of previous therapeutic irradiation to the breast region that, combined with
the proposed treatment, would result in an excessively high total radiation dose to a
significant volume is another absolute contraindication.

Multicentric cancer has been considered a contraindication to BCT. Recent studies
suggest low rates of IBTR in selected patients (<3 lesions, no extensive intraductal
component, all clinical and radiographic disease excised to clear margins). Several
older retrospective studies suggested that the risk of in-breast recurrence following
breast conservation for multicentric disease was unacceptably high, in the range of
25–40%. However, many of these earlier studies did not reach uniform standards in
terms of the use of RT or of margin assessment.

Contemporary investigations into the frequency of inbreast recurrence following
breast conservation in the setting of multicentric disease suggest that local control
equivalent to that seen with unifocal disease can be achieved with careful attention
to current standards of care. Where comparisons between mastectomy and breast
conservation are possible, the use of mastectomy does not seem to confer
                                                                           P a g e | 34


advantages in terms of local control or survival. These data are limited by small
numbers and retrospective analyses, but deserve attention and suggest the need for
well-designed prospective studies, especially since multicentric disease is an
increasingly frequent finding with the advent of magnetic resonance imaging (MRI)
of the breast, and the biologic importance such multicentric disease is unknown.

However, even if breast conservation is safe in women with multicentric disease, the
volume of resection required and the need to adhere to high local therapy standards
(e.g., free resection margins, the use of boost RT, particularly in young women) may
limit the practical application of breast conservation in the presence of multicentric
breast cancer. This accumulating evidence provides justification for prospective
studies to determine whether multicentricity should remain an absolute
contraindication to BCT.

Finally, persistent positive margins after reasonable surgical attempts absolutely
contraindicate breast-conservation treatment with radiation. The importance of a
single focally positive microscopic margin needs further study and may not be an
absolute contraindication.

Relative Contraindications
A history of collagen vascular disease is a relative contraindication to breast
conservation treatment because published reports indicate that such patients
tolerate irradiation poorly. Most radiation oncologists will not treat patients with
scleroderma or active lupus erythematosus, considering either an absolute
contraindication. In contrast, rheumatoid arthritis is not a relative or an absolute
contraindication.

Patients with multiple gross tumors in the same quadrant and indeterminate
calcifications must be carefully assessed for suitability because studies in this area
are not definitive.

Tumor size is not an absolute contraindication to breast conservation treatment,
although few reports have been published about treating patients with tumors larger
than 4 to 5 cm. However, a relative contraindication is the presence of a large tumor
in a small breast in which an adequate resection would result in significant cosmetic
alteration. Breast size can be a relative contraindication. Women with large or
pendulous breasts can be treated by irradiation if reproducibility of patient set-up
can be ensured and if 6-MV photon beam irradiation is technically possible to obtain
adequate dose homogeneity

Indications and requirements for breast-conserving surgery
                                                                            P a g e | 35


Breast conservation therapy is an appropriate method of primary therapy for the
majority of women with stage I and II breast cancer. BCT provides long-term
survival rates equivalent to those of total mastectomy while preserving the breast.
The risk of IBTR after BCT has decreased over time with improvements in
mammography and margin assessment, and (mainly) because of the favourable
interaction of adjuvant systemic therapy with RT. BCT requires the ability to deliver
full-dose RT. The risk for IBTR in the absence of RT has the potential to negatively
impact survival. Careful attention to patient selection and the technical details of
surgery and RT are important, because IBTR rates in excess of 10% at 5 years are
associated with increased breast cancer mortality at 15 years.



Nipple/areolar sparing mastectomy
Skin-sparing mastectomy is being offered with increased frequency to patients with
early breast cancer. Smaller skin incisions are used around the nipple-areolar
complex to preserve the breast envelope of skin. Multiple retrospective studies
report that local recurrence rates range from 0 to 7%, which is similar to historical
controls. The local recurrence rate seems to be related to the pathologic
characteristics of the breast cancer and stage of disease, not an inadequate surgical
excision. This can be combined with an SLN excision through usually a counter-
incision in the axilla.

The newest procedure to address women who need a mastectomy to treat their
breast cancer is a nipple-sparing mastectomy (NSM). Cosmetic outcome and patient
satisfaction following NSM are thought to be superior compared with standard
mastectomy. Studies have shown that with careful patient selection and pathologic
examination of the nipple/areolar complex at the time of surgery, NSM can be
oncologically safe in patients who prefer this technique as important for their quality
of life. In a German study of 246 women in which NSM was compared with modified
radical mastectomy, with a follow-up of 101 months, there were no significant
differences between the groups regarding local recurrences or OS. Patient selection
is critical, and NSM may be attempted in women who request prophylactic
mastectomy or in patients in whom the tumor is > 2.0 cm from the nipple. Women
should be aware that the nipple usually does not remain sensate and loses erectile
function after NSM



BCS after Neoadjuvant therapy
Neoadjuvant systemic therapy (also called primary systemic therapy or induction
therapy) has become a valuable strategy in the multidisciplinary treatment approach
                                                                          P a g e | 36


to breast cancer. Once reserved for women diagnosed with locally advanced or
inflammatory breast cancer, the tumor downstaging benefits of the neoadjuvant
therapy sequence are increasingly offered to women diagnosed with early-stage
disease as well. Most of the neoadjuvant studies reported to date have involved
delivery of chemotherapy as the induction therapy regimen.



One of the most important benefits of neoadjuvant chemotherapy is that it offers
tumor down-staging, expanding the number of women eligible for BCS. Typically,
tumors 4 cm in size or less are best suited for BCS, but the cosmetic results improve
with smaller tumors. Several large randomized controlled trials have reported the
effect of neoadjuvant chemotherapy on rates of BCS. Investigators for the NSABP
B-18 trial reported that women who received preoperative chemotherapy were
significantly more likely to receive a lumpectomy compared with women who
received adjuvant therapy (60% versus 67%, P0.002), with the greatest increase in
lumpectomy rates among women who had tumors larger than 5 cm. Other authors
have studied BCS in the setting of neoadjuvant chemotherapy with comparable
results.

From these studies, the rates of BCS range from 37% to 89%, but in general are
higher among women who received neoadjuvant chemotherapy. In fact,
approximately one-quarter of women who are not initially eligible for BCS, but who
receive neoadjuvant chemotherapy, may safely receive BCS following chemotherapy
because of tumor shrinkage. Singletary and colleagues reviewed the post-
mastectomy athology records of women who received neoadjuvant chemotherapy,
and reported that up to 23% of women became potential BCS candidates based on
based on resolution of skin changes, shrinkage of the primary tumor to less than 5
cm, and the presence of unifocal disease; however, it remains challenging to
accurately predict tumor size following neoadjuvant chemotherapy, with clinical
examination and current imaging modalities such as mammography and ultrasound
only moderately helpful in accurately predicting residual tumor size.

Nonetheless, BCS can be safely performed in women who receive neoadjuvant
chemotherapy, with low rates of loco regional recurrence. Early studies documenting
higher rates of breast tumor recurrence prompted scepticism in the ability of BCS to
safely treat these women, with loco-regional recurrence rates ranging from 3–24%
by ten years of follow-up. In general, reports of higher local recurrence rates were
observed in women with inflammatory or locally advanced disease at presentation,
and in patients where radiation-only was delivered as loco regional therapy (without
surgery) after neoadjuvant chemotherapy.

Chen and colleagues identified risk factors for loco-regional recurrence and
developed selection criteria for women who will be best suited for BCS following
                                                                            P a g e | 37


neoadjuvant chemotherapy. In this study (a collective review of the M.D. Anderson
Cancer Center experience with breast-conserving surgery after neoadjuvant
chemotherapy), approximately 9% of women developed loco regional recurrence.
Characteristics associated with increased likelihood of loco-regional recurrence
included larger tumor sizes, advanced nodal disease, a multifocal pattern of residual
disease following neoadjuvant chemotherapy, and the presence of lymphovascular
invasion.

The study authors propose the following contraindications for BCS following
neoadjuvant chemotherapy: residual tumor size greater than 5 cm, residual skin
oedema or direct skin involvement, chest wall fixation, diffuse calcifications on post-
chemotherapy mammography, multicentric disease, and contraindications to medical
therapy. Notably, T3 or T4 tumors did not have an increased risk of loco regional
recurrence if another contraindication was not present.

Patients with large tumours are not suitable to breast conserving surgery (BCS) for
obvious reasons. Instead, neoadjuvant or induction chemotherapy (NACT) is used to
reduce the primary tumour by transforming locally advanced lesions into early breast
tumours. Randomized trials have reported satisfactory downstaging rates between
49% and 94% with induction chemotherapy for operable breast cancer. However,
the safety of performing breast conserving treatment in such patients has not yet
been defined. The partial breast resection after neoadjuvant chemotherapy remains
controversial. This fact is based on the observation that tumour shrinkage patterns
are not concentrical. The microscopic residual tumour surrounding the post-
chemotherapy lump is the major objection to breast conserving therapy after NACT.

This observation led Veronesi et al. to propose quadrantectomy to all patients with
large tumours submitted to induction chemotherapy, regardless of clinical response.
On the other hand, three major points support the hypothesis that BCS is a safe
option for downstaged breast cancer patients. First, about 20% of patients achieve
complete pathological response. Second, there is significant evidence that
radiotherapy is able to sterilize the microscopic residual tumour. Finally, recent
studies concerning the efficacy of imaging diagnostics in predicting residual tumour
after neoadjuvant chemotherapy have shown that concentric tumour shrinkage is
the most common pattern of tumour regression in patients with partial response.



Local treatment after neoadjuvant systemic therapy
The neoadjuvant (preoperative, primary) use of cytotoxic, hormonal, and/or
trastuzumab therapy effectively reduces tumor burden in the breast and the axilla
without compromising survival. The risk of local recurrence is determined by the
initial clinical stage and the pathologic stage after neoadjuvant therapy. Neoadjuvant
                                                                            P a g e | 38


therapy is indicated in patients with inoperable tumors or if BCT is desired by
patients with large tumors otherwise requiring mastectomy. Patients with
multicentric tumors generally will not become candidates for BCT with this approach.
Initial multidisciplinary evaluation is important. The tumor site should be marked
before treatment (e.g., by clipping) to allow tumor localization at surgery. Multiple
imaging studies are not needed during treatment unless there is concern about
disease progression. Surgery is necessary in all patients, even those with a complete
clinical response. Any residual palpable or imaging-detected lesions should be
removed, but the entire initial tumor volume does not need to be resected in tumors
showing a reduction in size.

The optimal timing of sentinel lymph node biopsy in relation to neoadjuvant systemic
therapy in patients with a clinically lymph node-negative axilla is uncertain at this
time, and further study is required. The identification rate of the sentinel lymph node
appears to be lower after neoadjuvant therapy, but some patients may avoid axillary
lymph node dissection because of downstaging. Ultrasonography of the axilla in
clinically lymph node-negative patients is useful in identifying pathologically lymph
node-positive patients at presentation. In some cases, knowledge of the pre-
treatment lymph nodal status is useful for radiation planning. In patients with lymph
node-positive disease at presentation who become clinically lymph node-negative
after treatment, axillary dissection is recommended because of the high false-
negative rate of SNB in this circumstance.

Postoperative RT is recommended for all patients treated with breast-conserving
surgery and for all patients with initially lymph node-positive disease or with locally
advanced disease treated with mastectomy.

BCS and Locally advanced breast cancer
Locally advanced breast cancer (LABC) continues to be a significant problem in the
United States and a common breast cancer presentation worldwide. LABC generally
is defined by bulky primary chest wall tumors and/or extensive adenopathy. This
includes patients with T3 (>5 cm) or T4 tumors (chest wall fixation or skin ulceration
and/or satellitosis) and N2/N3 disease (matted axillary and/or internal mammary
metastases)

The magnitude of the clinical response to neoadjuvant chemotherapy in LABC
prompted investigations of breast conservation for selected patients. Initially,
whether the clinical response correlated with either a concentric diminution of the
initial mass or a primary tumor that left foci of malignant cells in the remaining
parenchyma was unclear. Singletary and colleagues conducted a feasibility study to
evaluate the pathologic extent of residual disease in 136 LABC patients treated with
induction chemotherapy. Extensive scrutiny of the post chemotherapy mastectomy
                                                                           P a g e | 39


specimens revealed that the residual tumor would have been amenable to
lumpectomy in approximately 25% of patients. From this and other studies, several
criteria for BCT in postneoadjuvant LABC have been adopted widely:

Patient desire for breast preservation

Absence of multicentric disease (tumors in different quadrants of the breast)

Absence of diffuse microcalcifications on mammogram

Absence of skin involvement consistent with inflammatory breast cancer

Residual tumor mass amenable to a margin-negative lumpectomy resection

Prospective, randomized controlled clinical trial data have confirmed acceptable rates
of local control among LABC patients undergoing breast-conserving surgery after
neoadjuvant therapy. Several prospective, randomized controlled trials of
neoadjuvant versus adjuvant/postoperative chemotherapy have included cohorts of
patients with Stage III disease/ LABC. Data from these studies have documented
acceptably low rates of local recurrence in LABC patients undergoing breast-
conserving surgery after neoadjuvant chemotherapy.

The NSABP B-18 investigators did note a trend toward higher local recurrence rates
among patients requiring preoperative downstaging in order to become lumpectomy
eligible (15% versus 7%). This is not necessarily surprising, however, as
postlumpectomy local recurrence is one manifestation of aggressive tumor biology,
and larger tumors are more likely to demonstrate aggressive behaviour, even after
mastectomy. Postmastectomy radiation (PMRT) is recommended for patients with T3
tumors because of this concept. Of note, the NSABP defines a negative margin as
the absence of tumor cells at the cut, inked specimen margin; wider margins are
probably preferable in patients receiving neoadjuvant chemotherapy.



Treatment of the Primary Site in Patients with Stage IV Breast
Cancer
The importance of effective local therapy as a means of optimizing survival in
women with stages 0–III breast cancer is well established. However, 5% of women
with primary breast cancer in the United States present with stage IV disease. The
traditional approach to this problem has been to treat with systemic therapy, and to
provide therapy for the primary tumor only when palliation is required. There is
presently no consensus regarding optimal local therapy for these women, and
treatment may vary from mastectomy, which is often justified as ‗‗toilette‘‘
                                                                             P a g e | 40


mastectomy and performed in order to prevent uncontrolled local disease during the
remainder of the patient‘s life, to obtaining a tissue diagnosis with needle biopsy.

According to the Fischer paradigm, once metastases have occurred, local therapy
provides no survival advantage, and should not be pursued. The Spectrum paradigm
is that the primary tumor is a source of re-seeding for distant sites, and therefore
elimination of this source of metastasizing cells may be of benefit. This model is
supported by level I data in metastatic renal cell carcinoma which show an
improvement in survival for patients undergoing nephrectomy, and by less stringent
data in several other organ sites. These findings raise the possibility that local
therapy for the intact primary tumor may contribute to prolongation of survival in
stage IV disease in other tumor types.

The past 10 years have witnessed a re-examination of the use of local therapy in
women with stage IV breast cancer, because an accumulation of retrospective data
suggest that local therapy for the primary site may also be important in this group of
women and may improve survival. At least nine retrospective studies (see Khan for
review) have examined the impact of surgical resection of the primary tumor in the
setting of metastatic disease, and eight shows a reduction in the hazard of death
ranging from 40% to 50%. Despite statistical adjustment for biases driving the use
of surgery, the improvement in survival seen in the surgical group cannot be
definitively attributed to the resection of the primary tumor since in most studies the
women in the surgical groups were younger, had smaller tumors, had fewer
metastatic sites, and were more likely to have bone/soft tissue metastases rather
than visceral disease.

Additionally, it is not possible from these retrospective studies to assess the value of
local therapy components other than resection of the primary tumor (i.e., axillary
dissection and local RT). There is also potential for harm from interruption of
effective systemic therapy in order to in turn deliver surgical and radiation therapy in
women with distant metastases. It is therefore necessary to conduct a randomized
trial to formally test the hypothesis generated by these retrospective reviews.



BCS & Receptor status
Triple-negative tumor status is defined by a tumor that is ER negative, PgR negative,
and HER2 negative. In a study reported by Solin et al of 519 patients after breast
conservation with radiation treatment, the 8-year rate of local failure was 8% for the
triple-negative subgroup compared with 4% for the non–triple-negative subgroup.
Other studies have also demonstrated an increased rate of local recurrence
associated with the triple-negative subtype, although this association has not been
                                                                          P a g e | 41


demonstrated in all studies. BCS can however still be utilised as long as the patient
is informed about the increased risk.




BCS & Ductal Carcinoma In-situ (DCIS)
The majority of women with DCIS or stage I or II breast cancer are eligible for local
therapy with breast-conserving surgery (BCS), mastectomy alone, or mastectomy
with immediate reconstruction.

Loco regional treatment of ductal carcinoma in situ. The risk of breast cancer death
after any treatment of ductal carcinoma in situ (DCIS) is <5%, but the risk of local
recurrence varies significantly by treatment. Mastectomy results in very low rates of
local recurrence, but does not appear to improve survival compared with BCT. The
contraindications to BCT listed apply to patients with DCIS, but neoadjuvant therapy
to reduce the size of larger DCIS lesions is not an option. Half of the IBTRs seen
after BCT for DCIS are invasive carcinoma, so minimizing IBTR is important. There is
no consensus on what constitutes an appropriate margin for DCIS treated with
excision and RT. As in invasive cancer, tumor-filled ducts not touching ink was the
only margin definition specified in prospective randomized trials.

Because DCIS, particularly low- and intermediate-grade lesions, may grow
discontinuously within the ducts, there is consensus that adequate negative margins
for DCIS should be larger than those for invasive carcinoma. A recent meta-analysis
indicates no reduction in IBTR with margins >2 mm in patients receiving RT32;
therefore a 2-mm margin was endorsed by the Panel as an appropriate standard.
Margins <2 mm are not an absolute indication for mastectomy, but should be
considered along with other factors influencing IBTR, such as the amount of DCIS
close to the margin, young patient age, and which margin is close. Anterior and
posterior margins of <2 mm are not of concern if there is no residual breast tissue.

All suspicious microcalcifications associated with the DCIS should be removed
surgically. Mammograms with magnification views are recommended if any
uncertainty regarding completeness of the resection remains after review of the
specimen mammogram and should be routine for patients with large areas of
calcifications. The only routine indication for SNB in DCIS is performance of a
mastectomy. In patients treated with BCT, SNB might be offered in selected cases at
higher risk for microinvasive disease (e.g., palpable masses). Whole breast RT is
recommended for the majority of patients, as it reduces the risk of local recurrence
by approximately 50%, and subsets not benefiting from RT have not been
prospectively identified.
                                                                           P a g e | 42


The strongest predictors for IBTR are age <40 years and positive margins of
resection. Exceptions to the use of RT might be elderly patients (particularly those
with low-grade DCIS) with wide margins. Retrospective, single institution studies
have suggested that a 1-cm margin might obviate the need for RT in DCIS.
Prospective attempts to duplicate single institution studies reporting low rates of
local recurrence after wide excision and detailed tissue processing have been
unsuccessful. In patients with hormone receptor-positive DCIS, treatment with
tamoxifen for 5 years reduces the risk of IBTR and contralateral cancer. The risk-
benefit ratio of tamoxifen varies with age and is most favourable in premenopausal
women. The use of aromatase inhibitors in DCIS is not recommended outside of a
trial.

Ductal carcinoma in situ is most commonly detected on routine screening
mammography as the finding of suspicious microcalcifications in an asymptomatic
woman. Most women with newly diagnosed DCIS are interested in breast
conservation treatment; therefore, one major decision for many of these women is
whether to add radiation treatment after surgical excision (lumpectomy).

In four randomized clinical trials, the addition of radiation treatment after surgical
excision (lumpectomy) reduced the risk of local recurrence by about 50%, both for
overall local recurrence and for the subset of invasive local recurrence. In three of
the four trials, the patients were randomized after lumpectomy to receive or not to
receive radiation treatment. The fourth trial from the UK/ANZ (United Kingdom,
Australia, and New Zealand) was a 2 × 2 factorial design to evaluate both radiation
treatment and tamoxifen. Two prospective randomized clinical trials have evaluated
adjuvant tamoxifen and have demonstrated that adjuvant tamoxifen reduces the
rate of all breast cancer events (ipsilateral plus contralateral) by about 25%-30%.
Of note, adjuvant tamoxifen does not substitute for definitive radiation treatment
after lumpectomy.

Notwithstanding the excellent long-term results for patients treated with
lumpectomy plus radiation treatment, and the significant improvement in local
recurrence associated with the addition of radiation treatment after lumpectomy,
ongoing studies have attempted to identify a subset of favourable DCIS tumors that
are sufficiently low risk for local recurrence so that omitting radiation treatment is
reasonable. Prospective randomized clinical trials have not reliably and reproducibly
identified patients at sufficiently low risk to avoid radiation treatment after
lumpectomy.

The Eastern Cooperative Oncology Group (ECOG) E5194 study was a nonrandomized
registration trial to attempt to prospectively identify a favourable subgroup of
patients with DCIS suitable for treatment with local excision alone, without radiation
treatment. The two nonrandomized arms of the study were specified as (A) low- or
                                                                         P a g e | 43


intermediate-grade DCIS, ≤ 2.5 cm in size; or (B) high-grade DCIS, ≤ 1.0 cm in size.
A minimum negative margin width of 3 mm was required on pathologic evaluation of
the excision specimen For the 565 patients with low- or intermediate-grade DCIS,
local recurrence at 5 years was 6.1%, and local recurrence at 7 years was 10.5%.
For the 105 patients with high-grade DCIS, the 5-year and 7-year rates of local
recurrence were 15.3% and 18%, respectively. The ECOG E5194 data suggest that
patients with high-grade DCIS tumors are not suitable for treatment with excision
alone without radiation treatment. For patients with low- or intermediate-grade
DCIS, the 5-year local recurrence rate is reasonably low (6.1%), although additional
follow-up will be needed to determine the longer-term results.


Conclusion
It is interesting to note that in most other organs (extremities, bladder, rectum,
larynx, or eye), acceptance of organ-conserving therapy into standard oncologic
practice has required only demonstration of feasibility and efficacy—not equivalency
with the radical surgical alternative. BCT, however, was not generally accepted as
standard oncologic practice until maturation of numerous prospective randomized
trials that universally demonstrated equivalence in disease control outcomes and
survival with mastectomy. In fact, acceptance of BCT as standard therapy in many
parts of the U.S. actually lagged more than a decade behind sentinel publications
documenting proof of equivalency with mastectomy. Even today, investigators
continue to search for a subset of breast cancer patients who will have better
disease control with radical surgery.

Nevertheless, BCT stands today as not only the best-studied example of
organconserving therapy, but also one of the most rigorously tested therapies in all
of medicine. Breast-conserving therapy requires a multidisciplinary approach with
close coordination among team members from diagnosis through surveillance after
treatment. The surgeon must be willing to assess and re-excise margins, to mark the
tumor bed with clips, and to use sentinel node biopsy in appropriate patients. The
radiation oncologist must be willing to use CT planning, paying close attention not
only to coverage of target tissues, but to avoidance of critical normal tissues.

The medical oncologist must work closely with the surgeon and radiation oncologist
to determine the optimal sequencing of therapies and selection of systemic agents.
All must recognize special circumstances where genetic counselling may be
beneficial, psychosocial support may be needed, or BCT may not be the best choice
for patients. When used appropriately, BCT produces maximal disease control and
quality of life while minimizing iatrogenic functional, cosmetic, and psychological
sequelae in patients with early-stage breast cancer. BCT serves as a model for the
                                                                          P a g e | 44


optimal combination of surgery and radiation therapy in organ-preserving cancer
therapy.




Research in the future
The recent Early Breast Cancer Trialists Collaborative Group Overview2 supports the
importance of loco regional control. The goal of future research should be to further
optimize and individualize loco regional treatment based on molecular or biological
markers that remain to be identified. Targeted systemic therapies have a major
impact on local control, and an improved understanding of the interaction between
local and increasingly effective systemic therapy is needed. As improvements in
imaging result in the identification of very small cancers that were previously
unrecognized, and as the development of molecular markers that provide greater
prognostic and predictive measures for local therapy become available, the rules
governing the selection of surgical therapy and the use of RT will need to be
reconsidered.

It is now clear that good local control of breast cancer helps to cure this disease.
Good local control is achieved by attention to surgical decision-making and technical
detail, appropriate use of RT, and optimal systemic therapy; all three modalities aid
local control. There now needs to be an intensive research effort directed towards
understanding the biology and clinical prediction of local failure so that local
treatment recommendations can optimally match our patients‘ priorities regarding
quality of life and breast preservation with strategy that delivers the best local
control. In addition, the concept that the primary tumor plays an important role in
disease progression, even after overt metastases are present, is evolving. It is
supported by substantial retrospective data, but needs to be demonstrated
prospectively in the unbiased setting of a randomized trial.
                                                                           P a g e | 45




References

1. Sakorafas GH, Safioleas M: Breast cancer surgery: An historical narrative. Part II.
18th and 19th centuries. Eur J Cancer Care (Engl) 2010;19:6–29(24).



2. Fisher B: Laboratory and clinical research in breast cancer—A personal adventure:
The David A. Karnofsky memorial lecture. Cancer Res 1980;40:3863–3874




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