A n a t o m y an d B re a s t C a n c e r

S t a g i n g : Is It Still Relevant?
Jennifer K. Plichta, MD, MSa, Brittany M. Campbell, BSa,
Elizabeth A. Mittendorf, MD, PhDb, E. Shelley Hwang, MD, MPHa,*

KEYWORDS
 Breast cancer  Staging  Prognosis  Biomarkers

KEY POINTS
 Anatomic staging for breast cancer continues to provide prognostic information relevant
to patients and clinicians.
 Prognostic staging for breast cancer now includes both anatomic factors and tumor-
specific factors, such as receptor status and genomic profiles.
 By incorporating tumor biology, the new staging system will likely improve the future
discrimination of prognosis between tumor stages.

WHY CLINICIANS STAGE PATIENTS

A patient’s breast cancer stage provides a concise summary of the disease at the time
of diagnosis and/or surgery. It conveys how much cancer is present, where it is
located, and highlights important tumor characteristics. It also allows for efficient
communication between clinicians and provides a framework for assessing and
relaying prognostic information based on the sum of the tumor and disease features.
By providing this prognostic framework, staging can be used to determine the best
treatment approach for individual patients. In addition to its patient-specific purpose,
it also forms the foundation on which changes in population-level cancer incidences
can be more thoroughly and accurately evaluated, by allowing assessment of the
overall impact of novel or changing breast cancer treatments. Staging information is
also frequently used to define groups for inclusion in clinical trials, facilitating
screening and evaluation of large groups of patients for research purposes.
To achieve these goals, the American Joint Committee on Cancer (AJCC) was orga-
nized in 1959 to develop a system of cancer staging using standardized language

Disclosure Statement: The authors have nothing to disclose.

a
Department of Surgery, Duke University Medical Center, DUMC 3513, Durham, NC 27710,
USA; b Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Cen-
ter, 1515 Holcombe Boulevard, Houston, TX 77030, USA
* Corresponding author.
E-mail address: [email protected]

Surg Oncol Clin N Am 27 (2018) 51–67

http://dx.doi.org/10.1016/j.soc.2017.07.010 surgonc.theclinics.com
1055-3207/18/ª 2017 Elsevier Inc. All rights reserved.
52 Plichta et al

acceptable to the American medical profession.1 During this era, aggressive local
treatments were standard (usually a radical mastectomy and postoperative radiation
to the chest wall for most patients with breast cancer), and effective systemic thera-
pies had not yet been established. Thus, the primary objective was to provide stan-
dard nomenclature for breast cancer prognostication to prevent futile care for those
likely to die from the disease. The guiding philosophy was to develop a classification
system that would convey the progression of the usual events that created the life
history of a cancer, including tumor growth (size) and spread (to regional lymph nodes
and/or distant organs).1 The AJCC used the principles of the TNM system (T, tumor;
N, nodes; M, metastasis), as described by the International Union Against Cancer
(UICC)2 to serve as the basis for categorizing the extent of disease. The aim was to
create a staging system that would allow physicians to determine treatment more
appropriately, to evaluate results of management more reliably, and to compare sta-
tistics from diverse institutions more confidently.1
Today, staging continues to be a critical tool used to communicate and understand
a patient’s breast cancer diagnosis, thus allowing for more accurate treatment discus-
sions and decisions. In today’s era of personalized medicine, breast cancer treatment
is leading the charge to incorporate more patient-specific and tumor-specific data into
determining a patient’s prognosis and thus customizing treatment decisions. As treat-
ments continue to evolve and improve, the staging system is also continuously being
refined.
Despite significant changes in breast cancer treatment, traditional anatomic TNM
staging remains relevant for several reasons. First, it allows investigators to continue
to study historic groups of patients and relate them to contemporary patients. Second,
it provides consistency in the way clinicians communicate with each other worldwide.
Last, it is often the only source of staging classification available in low-income and
middle-income countries and will likely remain the cornerstone on which evaluation
and treatment decisions are made.3 Moreover, early detection programs may be
the most effective tools for improving outcomes in these countries and TNM staging
directly reflects the success of such programs. However, in this modern era, many
treatment decisions for patients with breast cancer are not based solely on the
TNM stage. For example, local-regional treatments (eg, surgery and radiation) are
often influenced by multicentricity and tumor margins, in addition to tumor size and
nodal status. Similarly, endocrine therapy is routinely recommended for hormone re-
ceptor–positive disease and targeted therapies are frequently recommended for hu-
man epidermal growth factor receptor 2 (HER2)-positive tumors. Thus, modern
staging systems have moved toward incorporating molecular markers into the staging
classification system.

HOW CLINICIANS STAGE PATIENTS

Breast cancer staging is continually evolving, and it has been defined and updated by
the AJCC for over 4 decades; the AJCC Cancer Staging Manual, 1st edition, was
published in 1977.1 Grouping cancer cases into stages was derived from survival rates
being higher for localized disease compared with those in which the disease had
spread beyond the original site, initially referred to as early and late cases. The
AJCC Cancer Staging Manual was created to facilitate improved consistency in
describing the extent of the neoplastic disease present, and thus allow clinicians to
better determine appropriate treatments, more reliably evaluate the results of man-
agement strategies, and more accurately compare statistics or research outcomes.1
Although it will not be fully adopted until January 2018, the most recent edition (8th)
 Anatomy and Breast Cancer Staging 53

of the AJCC Cancer Staging Manual, was published in 2016 and includes 2 staging
systems: the anatomic stage and the prognostic stage.4 The anatomic stage includes
the traditional anatomic factors, the primary tumor size (T), nodal status (N), and
distant metastasis (M) based on clinical and/or pathologic assessments. However,
additional tumor characteristics have recently been added to the AJCC prognostic
staging system to more accurately determine the stage of a cancer, such as tumor
grade, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status,
and (when available) tumor multigene panel testing (ie, Oncotype DX, Genomic Health,
Redwood City, CA). Taken together, staging provides the most reliable source for
accurately predicting a patient’s outcome and, although anatomic staging may be pre-
dominantly used in some countries, prognostic staging is preferred for patients diag-
nosed and treated in the United States.
Determining a patient’s breast cancer stage typically starts with a physical exami-
nation to provide an initial evaluation of the extent of the cancer, such as the tumor
location, tumor size, and presence of regional and/or distant metastases. Imaging
tests are then used to confirm physical examination findings. This may include a
mammogram; breast or axillary ultrasound; breast MRI; computed tomography (CT)
scan of the chest, abdomen, or pelvis; nuclear medicine bone scan; and/or PET
scan. Depending on the examination and imaging findings, laboratory tests may be
sent to make additional assessments, such as blood tests and/or tissue biopsies.
When breast biopsies are performed, the pathologic assessment report routinely pro-
vides information on the tumor histology, grade, and receptor status (ER, PR, and
HER2). If axillary lymph nodes or suspicious lesions of distant organs are biopsied,
metastases may be identified.
The National Comprehensive Cancer Network guidelines for an invasive breast can-
cer staging workup include5
 History and physical examination
 Diagnostic bilateral mammogram
 Pathologic assessment review
 Determination of ER, PR, and HER2 status
 Breast MRI (optional).
Although many surgeons obtain a breast MRI with each new breast cancer diag-
nosis to more fully evaluate the extent of disease and rule out mammographically
occult disease, wide variation in MRI use is observed and misconceptions about
MRI benefits persist.6 In general, breast MRIs have not been clearly shown to improve
the surgeon’s ability to obtain negative margins7,8 or to improve recurrence or survival
rates.9,10 Similarly, routine axillary ultrasound to determine clinical nodal status is also
frequently used but remains controversial.11,12 The benefit of axillary staging by imag-
ing is to avoid 2-stage axillary surgery; however, the main disadvantage is for those
women who may have limited axillary disease managed via sentinel lymph node bi-
opsy with or without axillary radiation. Thus, no consensus currently exists on routine
use of breast MRI or staging axillary ultrasound.
For patients with early-stage breast cancer, consideration of additional studies is
directed by signs or symptoms, and systemic imaging is not routinely indicated.13
For patients with more advanced disease, additional studies to consider may
include14
 Complete blood count
 Comprehensive metabolic panel, including liver function tests and alkaline
phosphatase
54 Plichta et al

 CT abdomen or pelvis with contrast or MRI with contrast

 CT chest with contrast
 Bone scan or sodium fluoride PET-CT
 Fluorodeoxyglucose (FDG) PET-CT (optional).
Depending on when staging is assessed, breast cancer staging can be divided into
4 types:
1. Clinical staging relies on the physical examination, imaging tests, and biopsies of
affected areas. This designation is recorded with a lower case “c” before the
TNM staging categories.
2. Pathologic staging can only be determined after a patient has had surgery to re-
move the primary tumor and regional lymph nodes. These results are then com-
bined with the clinical stage to determine the final pathologic stage. This
designation is recorded with a lower case “p” before the TNM staging categories.
3. Post-therapy or postneoadjuvant therapy staging determines how much cancer re-
mains after a patient completes preoperative systemic therapy and/or radiation
therapy before surgery. This is often assessed after surgery, but it may incorporate
both clinical and pathologic staging information. This designation is recorded with a
lower case “y” before the TNM staging categories.
4. Restaging is performed if a cancer returns after treatment and is used to determine
the extent of disease recurrence. However, importantly, the formal stage of a can-
cer does not change over time, even if the cancer returns or progresses. Rarely, a
cancer may be restaged after a significant disease-free interval, which would
include the same assessments performed at the time of the initial diagnosis (ie, ex-
aminations, imaging, biopsies, and possibly surgery), and the new stage is re-
corded with a lower case “r” before the restaged TNM designation. A
contralateral cancer is staged as a new episode of cancer, with the exception of
direct tumor extension or dissemination via lymphatic spread.
When determining the anatomic stage, the categories for the primary tumor are the
same for both clinical and pathologic assessments4 (Fig. 1A; Table 1). The T stage
should include the prefix “c” for clinical stage or “p” for pathologic stage, as appro-
priate. Tumor size should be rounded up to the nearest millimeter and, when multi-
focal, the largest tumor focus is used for T categorization (multiple foci are not
added together). The additional suffix “m” can be used when the tumor is multifocal
and the prefix “y” can be used when the patient has received preoperative (neoadju-
vant) systemic therapy.
The categories for the regional lymph nodes vary between clinical and pathologic4
assessments (see Fig. 1B; see Table 1). Similar to the T category, the N category
should include the prefix “c” for clinical stage or “p” for pathologic stage, as appro-
priate. The additional suffix “sn” can be used when the lymph nodes have been eval-
uated by sentinel lymph node biopsy or “f” when the lymph nodes have been
evaluated by fine-needle aspiration (FNA) or core needle biopsy without further resec-
tion of the nodes. Category cNX is considered invalid for most patients and, if a pa-
tient’s clinical examination (and/or imaging) is negative, it should be more
accurately listed as cN0; the exception to this being patients who have had prior axil-
lary nodal clearance and cannot be evaluated by clinical examination or imaging.
To assess the M stage, clinical examination is used to classify patients as cM0 or
cM1 (see Table 1), and the designation pM0 is considered invalid.4 Patients who
are microscopically confirmed to have metastatic disease can be categorized as
pM1. Notably, M0 includes M0(i1). If a patient is deemed to have M1 disease before
 Anatomy and Breast Cancer Staging 55

Fig. 1. Clinical staging categories for the (A) primary breast tumor and (B) regional axillary
lymph nodes.4 For the primary breast tumor (A), tumor size is used for delineating
56 Plichta et al

preoperative systemic therapy, the patient is categorized as having stage IV disease

and remains stage IV regardless of response to therapy. However, the stage designa-
tion should be updated if postsurgical imaging (within 4 months of diagnosis) reveals
distant metastases, provided the patient has not received preoperative therapy.
For patients undergoing preoperative therapy, no pathologic stage group is
assigned if there is a complete pathologic response (pCR), although these patients
have been shown to have a significantly improved disease-free and overall survival,
as confirmed in a recent meta-analysis.15 However, when documenting staging for
patients who received preoperative systemic therapy and experienced a pCR, one
should continue to list the initial clinical staging information, as well as the pCR
status.
Histopathologic tumor types include in situ carcinomas (ductal carcinoma in situ,
Paget disease) and invasive carcinomas (ductal, inflammatory, medullary, medullary
with lymphoid stroma, mucinous, papillary, tubular, lobular, Paget with infiltrating, un-
differentiated, squamous cell, adenoid cystic, secretory, cribriform, and not otherwise
specified). For histologic grading, all invasive breast cancers should be assigned a
grade using the Nottingham modification of the Scarff-Bloom-Richardson grading
system. Tumor grade is determined by scoring 3 morphologic features: tubule forma-
tion, nuclear pleomorphism, and mitotic count. Each feature is assigned a score from 1
(favorable) to 3 (unfavorable), and the summation of the 3 scores determines the cate-
gory as follows:
 Grade 1 (low): 3 to 5 points
 Grade 2 (intermediate): 6 to 7 points
 Grade 3 (high): 8 to 9 points.

ANATOMIC STAGING, TUMOR GRADING, AND OUTCOMES

Although the anatomic extent of disease alone may not define the entire prognosis, it
has remained a key prognostic factor in breast cancer (Table 2). In 1969, Fisher and
colleagues16 evaluated more than 2000 subjects with operative breast cancer entered
into the National Breast Project by 45 institutions and reported that a larger tumor size
was associated with a decreased survival, increased recurrence rates, and an
increased likelihood of positive axillary lymph nodes. As such, tumor size was consid-
ered a key factor in breast cancer staging. Subsequently, a review of 24,136 female
subjects with breast cancer from a Breast Cancer Survey was carried out by the Amer-
ican College of Surgeons in 1978.17 Disease-free survival (cure rates) at 5 years were
60.5% for clinically localized disease and 33.9% for regional disease. Overall survival
rates at 5 years were 72.8% for localized disease and 49.1% for regional disease.
These findings confirmed that reduced cure and survival rates were associated with
an increase in the number of positive nodes; a correlation with tumor size and

=
T categories 1 to 3; however, chest wall involvement results in categorization as T4a disease,
whereas skin involvement via satellite nodules or ulceration is considered T4b disease and,
when both are present, the tumor is categorized as T4c. Inflammatory breast cancer is cate-
gorized as T4d disease (not shown). For the regional axillary lymph nodes (B), patients are
categorized as cN1 with metastases to movable ipsilateral level I to II nodes, whereas clini-
cally fixed or matted nodes in the ipsilateral level I to II axilla are considered cN2. For cN3
disease, patients have metastases to ipsilateral infraclavicular (level III axillary) nodes, or
to ipsilateral internal mammary nodes with level I to II axillary nodal metastases, or to ipsi-
lateral supraclavicular nodes. (Courtesy of Duke University. Illustrated by Lauren Halligan,
MSMI; copyright Duke University; with permission under a CC BY-ND 4.0 license.)
 Anatomy and Breast Cancer Staging 57

Table 1
The American Joint Committee Cancer Staging Manual, 8th edition, breast cancer definitions
of anatomic and pathologic staging guidelines

T Category T criteria (clinical and pathologic)

Tis Only ductal carcinoma in situ identified (no invasive component)
T1 Tumor size 2 cm in greatest dimension (using the largest tumor foci, if
multifocal)
 T1mi: tumor size 1 mm
 T1a: tumor size >1 mm but 5 mm
 T1b: tumor size >5 mm but 10 mm
 T1c: tumor size >10 mm but 20 mm
T2 Tumor size >2 cm but 5 cm in greatest dimension
T3 Tumor size >5 cm in greatest dimension
T4 Tumor of any size with direct extension to the chest wall and/or skin (ulceration
or macroscopic nodules); invasion of the dermis alone does not qualify as T4
 T4a: tumor extension to the chest wall; invasion or adherence to the pectoralis
muscle without chest wall invasion does not qualify as T4
 T4b: ulceration and/or ipsilateral macroscopic satellite nodules and/or skin
edema (eg, peau d’orange) that does not meet criteria for inflammatory
carcinoma
 T4c: both T4a and T4b are present
 T4d: inflammatory carcinoma
N Category N criteria (clinical)
cN0 No regional lymph node metastases (by imaging or clinical examination)
cN1 Metastases to movable ipsilateral level I–II axillary lymph nodes
cN2 Metastases to ipsilateral level I–II axillary lymph nodes that are clinically fixed or
matted, or to ipsilateral internal mammary nodes without axillary lymph node
involvement
 cN2a: metastases to ipsilateral level I–II axillary nodes that are clinically fixed
or matted
 cN2b: metastases to ipsilateral internal mammary nodes without axillary
nodal involvement
cN3 Metastases to ipsilateral infraclavicular (level III axillary) lymph nodes, to
ipsilateral internal mammary lymph nodes with level I–II axillary lymph node
metastases, or to ipsilateral supraclavicular lymph nodes
 cN3a: metastases to ipsilateral infraclavicular (level III axillary) nodes with or
without level I–II axillary nodal involvement
 cN3b: metastases to ipsilateral internal mammary nodes with level I–II axillary
nodal metastases
 cN3c: metastases to ipsilateral supraclavicular nodes with or without axillary
or internal mammary nodal involvement
N Category N criteria (pathologic)
pN0 No regional lymph node metastases identified or ITCs only
 pN0(i1): regional lymph nodes with ITCs only (malignant cell
clusters 0.2 mm)
pN1 Micrometastases, metastases to 1–3 axillary lymph nodes and/or clinically
negative internal mammary nodes with micrometastases or macrometastases
by sentinel lymph node biopsy
 pN1mi: micrometastases (>0.2 mm but 2 mm)
 pN1a: metastases to 1–3 axillary nodes, at least 1 metastasis > 2 mm
 pN1b: metastases to ipsilateral internal mammary sentinel nodes, excluding
ITCs
 pN1c: pN1a and pN1b combined

(continued on next page)

58 Plichta et al

Table 1
(continued )
pN2 Metastases to 4–9 axillary lymph nodes or positive ipsilateral internal mammary
lymph nodes by imaging in the absence of axillary lymph node metastases
 pN2a: metastases to 4–9 axillary nodes, at least 1 metastasis > 2 mm
 pN2b: metastases in clinically detected internal mammary nodes with or
without microscopic confirmation; with pathologically negative axillary
nodes
pN3 Metastases to 10 axillary lymph nodes, to infraclavicular level III axillary nodes,
to positive ipsilateral internal mammary nodes by imaging in the presence of
1 positive level I–II axillary nodes, to >3 axillary nodes and micrometastases
or macrometastases by sentinel lymph node biopsy in clinically negative
ipsilateral internal mammary nodes, or to ipsilateral supraclavicular nodes
 pN3a: metastases to 10 axillary nodes or to infraclavicular level III axillary
nodes
 pN3b: positive ipsilateral internal mammary nodes by imaging in the presence
of 1 positive level I–II axillary nodes, or to >3 axillary nodes and microme-
tastases or macrometastases by sentinel lymph node biopsy in clinically
negative ipsilateral internal mammary nodes
 pN3c: metastases to ipsilateral supraclavicular nodes
M Category M criteria (clinical and pathologic)
M0 No clinical or radiographic evidence of distant metastases (designated cM0,
never pM0); imaging studies are not required to assign the cM0 category
 cM0(i1): no clinical or radiographic evidence of distant metastases in the
presence of tumor cells or deposits  0.2 mm detected microscopically or by
molecular techniques in circulating blood, bone marrow, or other nonre-
gional nodal tissue in a patient without symptoms or signs of metastases
M1 Distant metastases detected by clinical and/or radiographic means (cM1), or
histologically proven metastases with at least 1 tumor deposit >0.2 mm (pM1)

Abbreviation: ITC, isolated tumor cells.

From AJCC Cancer Staging Manual. 8th edition. New York: Springer International Publishing;
2016.

prognosis was also noted.17 Similarly, review of 24,740 cases in the Surveillance,
Epidemiology, and End Results (SEER) program from 1977 to 1982 found that tumor
diameter and lymph node status were independent but additive prognostic indicators:
as tumor size increased, survival decreased regardless of nodal status; as nodal
involvement increased, survival decreased regardless of tumor size.18 Of note,
the study also suggested that lymph node status indicates a tumor’s ability to spread
but that lymph node involvement was not mandatory for distant disease
progression.18
Of 50,834 patients diagnosed between 1983 to 1987 in the SEER program, relative
survival data clearly demonstrated separation of the stages with an expected progres-
sion from the best (stage I) to the worst (stage IV) using the AJCC Cancer Staging
Manual, 4th edition, TNM staging system.19 This separation of stages was again
confirmed in the AJCC Cancer Staging Manual, 5th edition, in which survival rates
for 50,383 patients with breast carcinoma were classified by the AJCC staging
system. Clearly separate 5-year observed and relative survival rates were noted
for each stage with an expected progression from the best (stage I: 5-year observed
survival rate 87%, 5-year relative survival rate 98%) to the worst (stage IV: 5-year
observed survival rate 13%, 5-year relative survival 16%).20 At that time, numerous
prognostic parameters for breast cancer had been postulated with well-supported
literature for tumor size, regional lymph node involvement, metastasis, tumor
 Anatomy and Breast Cancer Staging 59

Table 2
Key references and findings in the history of breast cancer staging

Author, Y of Publication Select Highlights

Fisher et al,16  Larger tumor size is associated with decreased survival,
1969 increased recurrence rates, and increased likelihood of pos-
itive axillary nodes
McGuire,38  Between 50%–60% of ER positive breast cancers will
1975 respond to endocrine therapy, whereas only 8%–16% of ER
negative cancers will respond
Knight et al,26  ER absence is associated with earlier recurrence, indepen-
1977 dent of tumor size and lymph node status
AJCC guidelines,  Lower stage cancers have higher recovery rates and greater
1st edition,1 1977 survival time
 Tumor size (T), spread to local lymph nodes (N) and distant
metastases (M) are important staging factors; tumor grade
was recorded but not included in the TNM classification
Nemoto et al,17  Expected survival decreases linearly with increasing number
1980 of histologically positive axillary nodes, up to 21 positive
nodes
Clark et al,27  PR and ER positivity are both associated with increased time
1983 to recurrence and improved overall survival
AJCC guidelines,  Detection of cancers before direction extension or meta-
2nd edition,39 1983 static spread generally leads to improved survival
Slamon et al,28  HER2 gene amplification was a significant predictor of
1987 recurrence and overall survival, independent of other
prognostic factors
 For node positive disease, HER2 gene amplification had
greater prognostic value than hormonal receptor status
AJCC guidelines,  T3N0M0 5-y survival (76%) most closely matches stage II
3rd edition,40 1988 (75%) rather than stage III (56%), thus reclassified as stage II
Carter et al,18  Both tumor size and number of positive lymph nodes are
1989 independent, additive prognostic indicators
 Women with 1–3 positive lymph nodes have improved 5-y
survival compared with those with 4 1 positive nodes
Tandon et al,41  HER2 oncogene amplification is associated with significantly
1989 decreased DFS and 5-y OS
 Axillary lymph node status is the most important prognostic
indicator
Henson et al,23  Observed positive correlation between grade and stage
1991  Both stage and grade are useful prognostic indicators, and
provide the best prediction of outcome when used in
combination
AJCC guidelines,  Relative survival is directly correlated with AJCC stage (best
4th edition (SEER survival for stages 0-I and incrementally worse through stage
data),19 1992 IV)
Gusterson et al,31  Expression of c-erbB-2 is prognostically significant for node-
1992 positive breast cancer
Press et al,30  In node-negative women, HER2 overexpression is an
1993 independent risk factor for disease recurrence
 Subgroup analysis confirmed a persistent increased risk in
premenopausal and postmenopausal women, as well as ER
negative and small (T1a) tumors

(continued on next page)

60 Plichta et al

Table 2
(continued )
Author, Y of Publication Select Highlights
Press et al,29  HER2 gene amplification is an independent predictor of
1997 poor clinical outcome (in the absence of adjuvant therapy)
 HER2 gene amplification is a stronger discriminant than tu-
mor size in this population
AJCC guidelines,  5-y observed survival decreases as stage increases (stage 0:
5th edition,20 1997 92%; stage I: 87%; stage IIA: 78%; stage IIB: 68%; stage IIIA:
51%; stage IIIB: 42%; stage IV: 13%)
 5-y relative survival decreases as stage increases (stage 0:
100%; stage I: 98%: stage IIA: 88%; stage IIB: 76%; stage IIIA:
56%; stage IIIB: 49%; stage IV: 16%)
 Prognostic factors reviewed and literature support noted
for: tumor size, regional lymph node involvement, metas-
tasis, tumor histology, tumor grade, chromatin, tumor ne-
crosis, mitotic counts, thymidine labeling index, S-phase
flow cytometry, Ki-67, angiogenesis, and peritumoral LVI
Fitzgibbons et al,32  Axillary lymph node status is among the most important
2000 prognostic indicators for surviving breast cancer
 Increasing tumor size, number of positive axillary lymph
nodes, and grade are poor prognostic indicators in breast
cancer
AJCC guidelines,  Though data are not yet sufficient to incorporate histologic
6th edition,42 grade into TNM stage, it remains an important prognostic
2002 indicator
AJCC guidelines,  Increasing tumor size and number of positive nodes
7th edition (NCDB demonstrate progressively worse 5-y survivals
data),21 2009  5-y observed survival decreases as stage increases (stage 0:
93%; stage I: 88%; stage IIA: 81%; stage IIB: 74%; stage IIIA:
67%; stage IIIB: 41%; stage IIIC: 49%; stage IV: 15%)
Elston & Ellis (in  Revised grading criteria (Bloom-Richardson-Elston criteria)
UICC 7th Edition),43,44 provided more objective and reproducible grading results
2010  Using these criteria, grade was directly correlated with
prognosis: grade I tumors had significantly better survival
than grades II–III
Yi et al,22  Pathologic (anatomic) staging still associated with progres-
2011 sively worse 5-y disease-specific survival
 Stage I: 98.8%, stage IIA: 96.3%, stage IIB: 94.5%, and stage
IIIA: 88.6%
 Staging that included pathologic stage, nuclear grade, and
ER status was the most precise in predicting survival
Sparano et al. (TailorX  Women with T1-2, hormone receptor–positive, HER2
Study),34 2015 negative, axillary node-negative breast cancer that had a
21-gene recurrence score of 0–10 had a 98.7% DFS rate and
98% overall survival rate
Mittendorf et al,33  The Neo-Bioscore incorporates biomarkers and treatment
2016 response to determine prognosis in patients undergoing
systemic chemotherapy before definitive surgery
 Scoring included the previously defined CPS 1 EG staging
system (clinical-pathologic stage, estrogen receptor status,
tumor grade) and added ERBB2 status, which improved
prognostic stratification

(continued on next page)

 Anatomy and Breast Cancer Staging 61

Table 2
(continued )
Author, Y of Publication Select Highlights
Harris et al,35  Of breast tumor biomarker assays, evidence supports use of
2016 Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and
urokinase plasminogen activator and plasminogen activator
inhibitor type 1 in select subgroups
 Only ER, PR, and HER2 biomarkers should guide specific
treatment regimen decisions, although disease stage, co-
morbidities, and patient preference should also be
considered
Cardoso et al,(MINDACT  Assessed clinical risk (using Adjuvant! Online) and genomic
Study)36 2016 risk (using 70-gene signature) in women with early-stage
breast cancer
 Women with discordant disease (low clinical risk and high
genomic risk, or high clinical risk and low genomic risk) had
similar 5-y survival rates regardless of chemotherapy receipt
AJCC guidelines,  Prognostic factors (nuclear grade, ER status, and HER2 sta-
8th edition,4 2016 tus) create a risk profile (sum of scores 5 0–3) combined with
pathologic stage to create a new staging system
 5-y DSS and OS decreased as pathologic stage 1 risk profile
score increased (ie, path stage IIA 1 risk profile 0 5 100%
DSS and 96.8% OS vs path stage IIA 5 risk profile 3 5 91%
DSS and 88.2% OS)

Abbreviations: DFS, disease-free survival; DSS, disease-specific survival; LVI, lymphovascular inva-
sion; NCDB, National Cancer Database; OS, overall survival; SEER, Surveillance, Epidemiology,
and End Results.

histology, tumor grade, chromatin, tumor necrosis, mitotic counts, thymidine labeling
index, S-phase flow cytometry, Ki-67, angiogenesis, and peritumoral lymphatic vessel
invasion.
Recent studies confirm the continued importance of anatomic staging. Review of
211,645 breast cancer cases diagnosed between 2001 and 2002, and reported in
the National Cancer Database (NCDB), again demonstrated the significance of
increasing tumor size and nodal burden because both correlated with progressively
worse survival.21 With regard to overall survival and disease stage (as classified by
the AJCC Cancer Staging Manual, 7th edition), the 5-year observed survival rates
were 93% for stage 0 disease and only 15% for stage IV disease.21 Using a more
contemporary database of 3728 patients with invasive breast cancer treated at MD
Anderson from 1997 to 2006, pathologic (anatomic) staging was still associated
with a progressively worse 5-year disease-specific survival on univariate and multivar-
iate analyses: stage I, 98.8%; stage IIA, 96.3%; stage IIB, 94.5%; and stage IIIA,
88.6%.22 Importantly, the combination of pathologic stage, nuclear grade, and ER sta-
tus were the most precise in predicting survival, assuming proper multidisciplinary
treatment with appropriate use of chemotherapy and endocrine therapy.22
Although tumor grade was not officially incorporated into the breast cancer staging
system until the 8th edition, it has been recommended for reporting since the 1st edi-
tion in 1977.1 In 1991, survival rates for 22,616 breast cancer cases in the SEER data-
base were reviewed using both stage and tumor grade.23 Survival rates for those
with stage II, grade 1 disease were similar to those assigned stage I, grade 3 and
were better than those assigned stage I, grade 4 (which would now be included
with grade 3 tumors). These results suggested that combining histologic grade and
62 Plichta et al

breast cancer stage may improve the prediction of outcomes.23 This was again
confirmed in a more recent analysis of 161,708 patients in the SEER database.24
Schwartz and colleagues24 demonstrated that a higher histologic grade was associ-
ated with a progressive decrease in 10-year survival, independent of tumor size or
nodal status, thus confirming grade as a prognostic factor. Although some investiga-
tors have questioned the reproducibility of histologic grading, specific methodology
has been developed to address these concerns.25

EVIDENCE TO SUPPORT INCORPORATION OF BIOMARKERS AND IMPLEMENTATION

Tumor biomarkers have long been recognized as important prognostic factors in

breast cancer and, for the first time, the AJCC Cancer Staging Manual, 8th edition, in-
corporates tumor biology. The first biomarkers to be recognized as having prognostic
significance for breast cancer were the ERs and PRs. McGuire and colleagues26
demonstrated as early as 1977 that the ER was an important prognostic factor in
early-stage breast cancer, independent of anatomic staging factors. In 1983, both
the ER and PR were examined in 189 subjects receiving adjuvant therapy for stage
II breast cancer and it was found that the presence of either ER or PR was positively
correlated with disease-free survival.27 Studies such as these led to the recommenda-
tion that hormone receptor status should be routinely examined, to improve survival
predictions. In 1987, the HER-2/neu oncogene was recognized to confer a worse
prognosis in patients with early-stage breast cancer.28 These findings were later
confirmed in larger datasets of both node-negative29,30 and as node-positive patients
in the Ludwig Breast Cancer Study Group.31
In 2000, Fitzgibbons and colleagues32 published the College of American Patholo-
gists Consensus Statement 1999, which ranked factors as follows: category I, factors
with prognostic value and useful in clinical patient management; category II, factors
extensively studied biologically and clinically, but its value remained unvalidated;
and category III, all other factors not sufficiently studied to demonstrate their prog-
nostic value. Category I factors included TNM staging information, histologic grade,
histologic type, mitotic figure counts, and hormone receptor status. Category II factors
included HER2-neu, proliferation markers, lymphatic and vascular channel invasion,
and p53. Following this publication, subsequent revisions of the AJCC guidelines
continued to evaluate the potential incorporation of many of these category I and II
factors. These efforts have resulted in the addition of new prognostic staging cate-
gories, which for the first time includes a select group of molecular markers.4
Evidence has now accumulated to support the combination of tumor biology and
anatomic extent of disease demonstrating significant predictive synergy for breast
cancer prognosis, beyond anatomic staging alone. Investigators at MD Anderson
evaluated the performance of a risk profile, which included pathologic stage, tumor
grade, lymphovascular invasion, hormone receptor status, and HER2 receptor sta-
tus.22 The incorporation of biomarkers yielded superior stratification of breast cancer
specific survivals compared with TNM staging alone. These findings were confirmed
by Winchester and colleagues,4 who evaluated 238,265 women diagnosed with inva-
sive breast cancer in 2010 to 2011 with a median follow-up of 37.6 months. Notably,
patients with triple-negative cancer (all grades) had a worse survival, which was
comparable to those at least 1 stage higher in the AJCC Cancer Staging Manual,
7th edition. Furthermore, several ER-positive or PR-positive subgroups (regardless
of HER2 status) had a better survival than those with the same 7th edition stage
group.4 Recently, the MD Anderson group has built on their previous experience to
develop the Neo-Bioscore, which incorporates biomarkers, as well as treatment
 Anatomy and Breast Cancer Staging 63

response, to determine prognosis in patients who undergo systemic chemotherapy

before definitive surgery.33 Thus, there is evidence to propose that future staging sys-
tems should incorporate treatment response, as well as staging at diagnosis.
The breast cancer field has been replete with studies to support multigene panel
testing for prediction of both prognosis and response to therapy. To date, the Onco-
type DX assay has been tested in the largest prospective validation cohort. Among
10,253 women enrolled in a prospective study, 1626 women had a recurrence
score of 0 to 10 and received endocrine therapy alone (without chemotherapy). At
5-year follow-up, this group had a distant disease-free survival of 99.3% (95% CI,
98.7–99.6), confirming the ability of this test to identify with high accuracy a group
of patients who had an excellent outcome with endocrine therapy alone.34
More recently, an American Society of Clinical Oncology panel convened to provide
guideline recommendations on the use of biomarkers for decision-making regarding
systemic therapy for women with early-stage breast cancer.35 After extensive review
of published evidence, the panel concluded that in addition to ER, PR, and HER2 re-
ceptors, additional assays, including Oncotype DX, EndoPredict (Myriad Genetics,
Salt Lake City, UT), PAM50 (Nanostring Technologies, Inc, Seattle, WA), Breast Can-
cer Index (Biotheranostics, San Diego, CA), and urokinase plasminogen activator and
plasminogen activator inhibitor type 1, had clinical utility for making adjuvant treat-
ment recommendations. Based on these and other recommendations, the AJCC Can-
cer Staging Manual, 8th edition, includes the Oncotype DX score (level I evidence) and
the MammaPrint (Agendia Inc, Irvine, CA), EndoPredict, PAM50, and EndoPredict
scores (level II evidence) as part of the staging for newly diagnosed breast cancers.
Following publication of the AJCC 8th edition guidelines, the MINDACT (Microarray
in Node-Negative and 1–3 Positive Lymph Node Disease May Avoid Chemotherapy)
trial reported that women with early-stage breast cancer and a low genomic risk
(based on a 70-gene signature, MammaPrint) but high clinical risk (as determined
by Adjuvant! Online) had similar 5-year survival rates regardless of chemotherapy
receipt.36 Survival rates were also similar for women with a high genomic risk and
low clinical risk. These findings suggest that chemotherapy may not be significantly
beneficial for women with discordant clinical and genomic risks (ie, high clinical risk
and low genomic risk, or low clinical risk and high genomic risk).36 Thus, in a summary
of the changes to the AJCC Cancer Staging Manual, 8th edition, Giuliano and col-
leagues37 reported that these findings are consistent with downstaging selected tu-
mors with low-risk genomic profiling and would likely be incorporated in future
updates to the manual.
For the of the AJCC Cancer Staging Manual, 8th edition, the new prognostic stage
groups were determined based on breast cancer populations from the NCDB that
were offered and mostly treated with appropriate endocrine and/or systemic therapy.4
This highlights not only the importance of tumor and disease characteristics but also
the critical need for appropriate multidisciplinary treatment. The authors recently per-
formed an analysis comparing the 7th edition to the revised 8th edition AJCC staging
system in 501,451 women in the NCDB diagnosed in 2004 to 2014, excluding patients
undergoing neoadjuvant chemotherapy (Table 3). In this analysis, we found that
19.3% of women stages I to III will be upstaged and 23.8% will be downstaged,
with the largest proportion of downstaged patients seen in the stage IB group
becoming stage IA (9175, 76.7%). By providing a staging system that better reflects
the current understanding of tumor biology and targeted therapy, this restaging is ex-
pected to provide a more accurate prediction of patient outcome. Work is ongoing to
determine whether this expectation can be validated in large population-based data-
sets treated with contemporary systemic therapy regimens.
 64
Plichta et al
Table 3
Implications of the American Joint Committee on Cancer 8th edition staging guidelines, comparing 7th edition and 8th edition in patients in the National
Cancer Database from 2004 to 2014

AJCC Guidelines 8th Edition Prognostic Stage

0 (%) IA (%) IB (%) IIA (%) IIB (%) IIIA (%) IIIB (%) IIIC (%) IV (%) Total (N)
0 100 0 0 0 0 0 0 0 0 6955
7th Edition, Pathologic
or Anatomic Stage

IA 0 86.5 3.9 9.6 0 0 0 0 0 304279

AJCC Guidelines,

IB 0 76.7 15.2 8.1 0 0 0 0 0 11,970

IIA 0 44.8 27.1 5.3 6.5 16.3 0 0 0 115819
IIB 0 0 27.8 0 1 25.7 14.4 31.2 0 16,982
IIIA 0 0 3.5 8.4 39.8 3.1 29.3 15.9 0 27,845
IIIB 0 0 0 0 0 5.8 35 59.2 0 3360
IIIC 0 0 0 0 0 6.1 39.7 54.2 0 11,458
IV 0 0 0 0 0 0 0 0 100 2783
Total (N) 6955 324249 50,885 38,628 18,739 24,967 16,328 17,917 2783 501451

Black shading represents patients with no change in their stage, light grey represents patients that were downstaged, and dark grey represents patients that were
upstaged. Each percent is per row total for each stage using the AJCC 7th edition, then restaged based on the 8th edition (each cell contains row percent). Total
from each column or row contains patient sample sizes for each stage. Overall N 5 501,451. Patients who did not have a corresponding prognostic stage in the 8th
edition were excluded.
(Data from Plichta and colleagues, unpublished data, 2017.)
 Anatomy and Breast Cancer Staging 65

SUMMARY

The AJCC staging system continues to provide a universal, efficient, and consistent
basis on which to communicate those factors that influence patient prognosis and
treatment recommendations. The 8th edition of the AJCC staging system incorpo-
rates, for the first time, molecular biomarkers that have been validated to have critical
prognostic significance. With these recent updates to the AJCC staging manual, clini-
cians are strongly encouraged to use the prognostic stage groups, including these
additional variables whenever possible. These advancements in the understanding
of the biology of breast cancer will undoubtedly continue to serve critical roles in
the ongoing refinement of breast cancer staging and to advance both patient care
and research.

ACKNOWLEDGMENTS

We would like to acknowledge and thank Lauren Halligan for her contributions in
preparation of the figure for this article. We would also like to acknowledge and thank
Samantha Thomas for her contributions in preparation of the data table summarizing
the restaging of patients.

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