Breast CA Management Principle for PG, UG

Breast CA Management Principle for PG, UG

1. National Comprehensive
NCCN | Cancer Network”

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3. NCCN |

pr tesemue

er

29. (oe een) Dell ni
rere

38. Tors | oI
(en aes

41. ri

43. Results Interpretation! Highly Unusual ER-Negative Results | Highly Unusual ER-Positive Results |

ing ER testing by Report As:

lated IHC assay)

49. ST No margin necessary

60. | Dose | Regimen

EBRT APBI

Brachytherapy APBI (including balloon/interstitial)

70. gative

72. ER2-Negative

74. HER:

76. HER:

78. Alona

85. menopausal or
Premenopausal Receivin ian Ablation or Suppression

irst-Line Therapy -ond- and/or Subsequent-Line Therapy

Plica
A a

88. HR-Positive and HER2-Negative with Visceral Crisist or Endocrine Refractory

89. ncer; TNBC)

91. nic Chemotherapy for Hi ive or -Negative and HER2-Negative®

92. ted with FDA-Approved Therapie

93. Biomarkers As:

jated with FDA-Approved Therapies

94. en |

Breast Cancer [Emerging Detection! Potential Targeted NCCN Category | NCCN Category of
Subtype Biomarkers Therapy"! of Evidence Preference

124. NCCN Categories of Evidence and Consensus

Category 2A Based upon | | evidence, there is uniform NCCN consensus (285% support of the Panel) that the
intervention is appropriate.

Category 3 d upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

NCCN Categories of Preferen

Other recommended Other is that m som

iterven or sig s affordable for simi

125. National

and adjuvant) was

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Porc llenen

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en

126. ES

National
Comprehensi
Can

Network

| N Clinical
fouidelines®) for Breast Cancer

ht of patients with carcinoma in
Le, Phyllodes tumor, inflammatory
| er during

| developed and are updated

Hof representatives'from NCCN
cused expertise in the fields of
ation oncology, pathology,

{that advances the goals of

ICN Guidelines endeavor to use
anti-racist anti-classis

pnd anti-weight-biased; and

‘ations and gender identities.

red language, instead focusing

E language is both more accurate

Hress the needs of individuals of

jes. NCCN Guidelines will

female, and male when citing

Guidelines Update Method]

Literature Search Criteria 4
Methodology.

Prior to the update of this version
Cancer, an electronic search of th
obtain key literature using the foll
Breast Neoplasms, DCIS, Inflamm
¡The PubMed database was chose]
resource for medical literature and]
literature.

The Search results were narrowed}
published in English. Results we
Clinical Trial, Phase Ill; Clinical Tri

Controlled Trial; Meta-Analysis; S)
Studies.

The potential relevance of thé Put}
from key PubMed art

Guidelines update meeting as well
deemed as relevantto these Guid
been included in this v

127. National

Comprehensi
Network'

United States in 2

if DCIS inclúdes history and
mammography, pathology
‘eceptor (ER) status, and MRI, as

H endorses the College of
lr both invasive and noninvasive

br ER status in order to determine
or tisk reduction. This is in
I Clinical Oncology (ASCO)/CAP
sting of newly diagnosed DCIS to
Iherapies for breast cancenrisk
) testing be considered optional
gnostic significance in invasive
ben established. To date, studies
ce of HER2sstatus as a
jatistically significant benefit to the
ation in HER2-amplified DCIS."

DCIS.‘ Ina prosp

DCIS who.undenwent both mamm|
preoperatively: 93 (56%) patients
153 (92%) were diagnosed by Mi
high-grade DCIS, 43 (48%)

were diagnosed by MRI alone."
can overestimate the extent of dis
for performing a mastectomy for D}
‘indings alone. If MRI findings sug}
seen on mammography such that
for complete excision, the findings]
MRI-guided biopsy of the more ex]
performed to determine w

and decreases local recurrence in
results, While several studies sug
patients with pure DCIS undergoin
following MRI compared with thos
MRI,'** some have demonstrated
of preoperative MRI for DCIS. 81°
detection rate of 6.2% with preope]
preoperative MRI remains controv
only performing breast MRI for DC

128. National

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[The goal of primary therapy for DCIS is to prevent progression to invasive]
breast — Management strategies for DCIS treatment include]

surgery (mastectomy or BCS), and/or radiation therapy (RT), followed by]
[adjuvant endo therapy in eligible patients to reduce risk of recurrence.

¡pact overall disease-related
lences for risk reduction must be

[pure DCIS have shown that the
Ir BCS decreasesthe rate of
distant metastasis-free

jan overall survival (OS) benefit.
17 trial showed that at 15 years,
ral invasive recurrence compared
330.69, P < .001).** The OS
hrough 15 years were similar
1.48)” Similar
ptional study of the SEER
[with DCIS.*” ina subgroup
'eated with BCS, with or without

SCA MATO, o
‘SEER database including 140,366
cancer mortality rate was 1
therapy (BCT) versus 2.3% for pat
95% CI, 0.67-0.88; P<

reduction in breast cancer mortalit
BCS alone

RT Boost: The use of RT boo:

but statistically significant reductio
(IBTR) risk (4% at 20 years) in all
cancers.

A pooled analysis of patientlevel
evaluated outcomes of pure ocis}
WBRT (n = 4131) who either recel
Gy (n= 2661) or received no boog
patients Was 9 years. A decrease |
received a boost compared with th 1
96.3%), 10 years (94.1% vs. 92.5
0389 for all). The use of RT boost
decreased IBTR across the entire]

129. National

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ized phase III trials are studying
pin patients with DCIS
10236 and NC
are now in active follow-up. A
ality of life (HRQOL) in patients
pse Ill ral (NCT00470236)
status was impacted negatively
| 19 the importance of informed
n of boost until data related to
lublished.2* According to the
¡ear data from this trial, presented at the 2021 annual San Antonio Brea:
SABCS) meeting, 93% of patients in the group
from local recurre ith
% in the group who received an RT boost (HR, 0.47; 95% Cl, 0.31—
(0.72: P 1). red publication of these data is awaited.

it WERT: RT a
cts. Therefore, in an attempt to
and preserve quality of life
Ession of RT in carefully selected

fp that selected patients have a

on tumor grade, size, absence of
at diagnosis.

A multiinstitutional. non=randomiz|

some support for BCS alone
onto one of two I
tumor size <2.5 cm (1

1
received tamoxifen. Of note, marg]

in protocol requitement in many]

median follow-up of 12.3
14.4% for low-intermediate-grade|
003). This suggests that IBTR eve
in the seemingly low-risk populati

The RTOG 9804 trial investigated
of low-risk DCIS, randomizing 634
RT or Observation after surgery

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rospective randomized
le whether wider margins can
Is from a retrospective study of

Ependent predictor of local
sing local recurrence risk with
Ent with margins <1 mm

is of 4660 patients with DCIS

compared with margins of 2 mm,
bbserved when margins of >2 mm
mm margins.*

with WBRT is associated with low
consider in. assessing adequacy o]
residual calcifications, which marg
posterior against muscle vs. medi
expectancy of the patient. Notabl
with invasive carcinoma, the
Margins for invasive breast cancel]
tumor on ink” as an adequate mar]
noninvasive components in this ml

Mastectomy: Patients with DCIS |
disease involving two or more qua]
otherimaging, physical examinati
5 patients undergoing mal
location that could/com
the axila (eg, tail ofthe breast), af
procedure should strongly be cong
to avoid necessitating a full axilla |
evaluation of the axilla.5*** Since ]
25%) with seemingly pure DCIS of
cancer atthe time of the definitive)
require axillary lymph node (ALN)

131. National
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featment options for patient:
es of consensus are:

(category 1)-Vhile considering

nmends an individualized

id other factors such as longevity.
hing BCS reduces IBTR rates in
ptients treated with BCS alone
width, the risk of IBTR is

xcision followed by WBRT (even
patients)

IB with optional reconstruction

plients (category 2A). According
DCIS may be considered
of the definition of RTOG 9804

recurrence? For patients with
ith negative margins and
II be receiving endocrine ther

According to th NCCN Panel, col
by analysis of margins and speci

mammography can be considered]
the excision remains (eg, the mas
clearly within the specimen), Clips
and ensure adequate coverage wi
‘APBI fields, and provide markers

pending the pathologic margin sta

For patients with pure DCIS treatel
description of any tumor close to

atleast 2 mm is associated with a
narrower negative margin widths,

margins >2 mm to further improve}
evidence. When there is only mini
margin, clinical judgment should b
excision with risk of recurrence for

For patients
of margin width; there ‘is a substan
with excision and WBRT, even in
‘the optimal margin width for treat

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huctal hyperplasia (ADH) and
Lirum of breast proliferative
Étion Trial performed by NSABP
€ of invasive breast cancer in
7/These data also showed that
the risk of developing invasive
y Trialists Collaborative Group
Ih 5 years of tamoxifen
ptor-unknown invasive tumors
bf recurrence of invasive breast

Jenefit from tamoxifen for patients
hservation surgery-and RT. In that
[ed with BCT were randomized to
in follow-up of 13.6 years,

4% absolute reduction in

(HR, 0:30; 95% Cl, 0.21-0.42; P
contralateral breast cancers (HR,
e patients receiving tamoxifen had
jasive and 5.6% for noninvasive

or no WBRT. and tamoxifen versus

events (HR, 0.71; 95% i, 0.58-of

lecreased ipsilateral and contralal
given WBRT (ipsilateral HR, 0.77:
0.27; 95% Cl, 0.12-0.59), but not
0.93; 95% Cl, 0.50-1.75; P = 80:
249; P= 1.0),

The standard dose of tamoxifen is}

TAM-01 trial studied a lower dose!

patients with breast intraepithelial

carcinoma in situ (LCIS), and ADH. The rate of recurrence of either
intraepithelial neoplasia or invasive breast cancer was 5.7% among thos
receiving tamoxifen 5 mg daily versus 11.9

(HR, 0.48; 95% Cl, 0.25-0.89) at a median foll

relative risk (RR) reduction with low

trials is consistent with that seen in trials th
tamoxifen, but the rate of sev

used a higher d
'e toxicity compared with placebo \

Anastrozole: In patients with ER-p]

by wide local excision with or with

133. National
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ts were stratified by age—<60
It was breast cancer-free
in an overall statistically
interval events compared with
P = .0234). The significant
between the two treatments was
br follow-up. The estimated

[
[
|
il
i
i
i
i
Fast cancer-free interval was

in the anastrozole group.** In
nprovement in breasticancer-free
nts (<60 years of age). With
idence of thrombosis or

pup while the anastrozole group
myalgia

nanagement of therapy-related complication:

NCCN Recommendations for Ma!
Treatment

with BCT, endocrine therapy with

postmenopausal patients) or an ai
postmenopausal patients, especi

‘with concerns of embolism) may b
risk of ipsilateral breast cancer red
undergoing BCT followed by RT; q
excision alone). The benefit of eng
not known. Low-dose tamoxifen q
the 20-mg standard-dose of tamoy
algorithm).

Follow-up of patients with DCIS in|
examination every 6 to 12 months}
as yearly diagnostic mammograpiy
follow-up mammogram should be
ompletion of RT (category 2B) (sl
receiving endocrine therapy for ris}
described in the NCCN Guideline:

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Inction tests (LFTs) have no
Ing metastatic disease in patients
hcers.** In addition, monitoring of
is not recommended.

mammography is
$ recommended only if necessary.

ntroversial. Breast MRI
lation of extent of disease,
se breasts where

e likely to elude preoperative
jas a high percentage of
diagnostic workup— including
[ces 57 MRI findings tend to
\g in increased frequency of

lo verify true malignant disease
[se mastectomy rates by
«cult disease that may have been
'S had the disease remained

Breast MRI may assist
occult primary tumors presenting ¥
Patients with Paget diSease not id
may help determine the extent of
in screening patients with higher t
history.”

If breast MRI imaging i
team experienced with reading brd
biopsy, and multidisciplinary mand

According to the NCON Panel, th
universally recommended by expe]
for staging evaluation to define e
neoadjuvant setting, to detect the |
cancer in the ipsilateral breast, or
cancer at time of initial diagnosis. À
include: cinica axillary metastasig
disease of the nipple:

imaging modalities or physical ex]
patients with prior mammographic

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mends testing for Ki-
adjuvant abemacicib.

rit history, prior breast
fpgnancy status, characteristics of

ammographically detected

h nodes, presence of

ality, and any prior treatment
should be oriented

for determination of biomarkers
lunambiguous standards for

pm both national'and local
thology reports for breast cancer
[case management." Significant.

ort surgical margins and failure
HAP has developed pathology
land standardized reporting of

The checklists.are available
Consistent,

Distress Assessment: Levels of di
be addressed individually. Psycho}
image and other factors. Younger
psychosocial distress than patient
NCCN Breast Cancer Panel recon
patients newly diagnosed with bre

Guidelinesfor Di Managem:

guidance.

Numerous epidemiologic studies #
after treatment for invasive breast
recurrence or death from breast c4
after treatment for breast cancer d
defects or other serious childhood
cancer, especially with cytotoxic a
may wane during the 5 to 10 year

136. National
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of the patient, risk of premature
and duration of chemotherapy
timing and duration allowed for

lity discussion among female
ted /ASCO guidelines stating that
hsideration for discussion of

[ding parity, prognosis, age. and

El recommends that all treating
their patients of childbearing

Y preservation. Patients who
rapy should be referred to a

[
ll
|
lc (chemotherapy or endocrine)

Jat GnRH agonists (such as
Ichemottierapy and then
chemotherapy protect against

192 In one trial

past cancer. 0° Smaller historical
[cise

Combining the various modalities
odds of preservation of future ferti
patients actively avoid becoming pl

Additional Diagnostic Workup
The Panel has reiterated that routil
patients with early-stage breast c:
of metastatic disease. Recommen
should be performed for those pat
for metastatic disease, based on |
benefits witirmetastatic workup in}
metastases were identified by bor
patients with stage |, Il, and III di
metastasis was detected by liver
patients with stage | or Il di
cancer, the prévalence of a positiv

6 and 7%,

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prd staging studies are-equivocal
helpful in identifying

or distant metastases when used
Ihe routine use of FDG-PETICT
bing of clinical stage |, Il, or

P its high false-negative rate for

[| cm) and/or low-grade disease,
tients without locally advanced
pf axillary nodal metastases, and

detectable metastatic

D or cN+, MO Disease

cancer initially undergo upfront

land adjuvant systemic therapy if

pteristics, such as tumor size,

aus expression of HER2

‘ome patients with early-stage operable

e disease may be treated with preoperati
by surgery. For NCCN Panel

reoperative systemic therapy,

HER2-positive or triple-negat
Isystemic therapy first, followe

[The optimal choice of surgery is based on

1s BCT in regards to long-term survival, risk]
all QOL |

urrence, and the impa

Breast Conserving Surgery

BOS allows patients to preserve tH
outcome. BCS is contraindicated
require radiation during pregnancy
malignant-appearing microcalcific
widespread disease that cannot b
single region or segment of the br
result: have diffusely positiv

contraindications to lumpectomy it

chest wall; active connective tissul

scleroderma and lupus); persisten
vith a known or suspe«

may have-an increased risk of ips!
breast cancer with BCT or

(category 2B).

Several studies of patients with e:

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f a Unilateral breast cancer,

Ir from 1998 to 2003 showed that
lerformed at the time of treatment
a reduction in breast

r (HR, 0.68; 95%
east cancer survival for this
tralateral risk-reducing

7%, difference ="4.8%), 1%
ve analysis could be due to

p risk-reducing contralateral

val Outcomes after risk-

lg patients with stage | or Il breast

It the absolute 20-year Survival
jastectomy was <1% among all

consider additional risk reduction

varian, and Panc
breast to a know

Margin Assessment. After surgical
assessment of resection margins |
benefit of BCS is predicated on a
after resection. The NCCN Panel
outlined in the guidelines establist
for negative surgical margins for i

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Axillary status is important for plan
RT. The lymphatic pathways from
mammary, infraclavicular, and/or

g surgery, the Panel
be diréctionally oriented and that

Traditional level | and Jevel II ALN
be provided for pathologic evaluat
ALND should be extended to inclu}
apparent in the level ll-and | node:
level I nodes, lymph node dissect
axillary vein from the latissimus dí

of the pectoralis minor muscle (le

e gross and microscopic margin
Itype of tumor (invasive cancer or
in. Marking the tumor bed with

fadiafion boost field, where

Historically, ALND has been the standard of care for axillary stagin:
However, ALND is associated v

Jargins unless it is DCIS-M, which 1 ditiag 132-100 This has been lal

margins are recommended. In

SLN mapping injections may be p

SLNs can be assessed for the pre|
hematoxylin and eosin (H&E) stai

immunohistochemistry (IHC). The
is negative by H&E staining but p 1
Because the historical and clinical
are based have relied on H&E stal
routine cytokeratin IHC to define

jot be applied directly to patients
local recurrence are more limited

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¡ate axillary dissection and the
entinel node was involved:
10 difference in OS’and DFS."

lucted between 1999 and 2004,
preast cancer <2 cm to either

pea only ifthe SLNwas

p. OS and DFS weressimilar in the
bis of this study showed patients
jorbidity and significantly more
paired QOL. "5."

patients (n= 1031) with SLNB.
dema and sensory loss were
drainage use, hospitalization,
longer in ALND compared to the
BCCG trial" also showed less

, it was clarified that for negative

role of ALND in those with a
y positive lymph nodes from an.

significant difference in local recur
arms (P= .13).'5° Th
recurrences at 10 ye
ALND and 1.5% (5 patients) in th
28)' The 10-year cumulative in
6:2% with ALND and 5.3% with SI

The results of the ACOSOG Z001
benefit to ALND in patients with eg
one or two SLN metastases (mini
receiving WBRT as part of BCT.
the ACOSOG 20011 trial since thd
radiation,

Another randomized trial (IBCSG
compare outcomes in patients wit
treated with ALND versus no ALN|
was limited to those undergoing B
undergoing mastectomy (9%) !*

plus ALND versus the group that 1
differences in 5-year DFS (84.4%;

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i
Bd patients (n = 4823) with T1 or

homized to an ALND or axillary
ve patients had positive SLNs
ich included a small fraction of
hy (17%) The results reported
ients randomized to ALND
IS was 86.9% (95% Cl, 84.1—
[B-85.5) in the axillary RT group.
p-95.0) in the ALND group and
p.'%* At the end of 5 years,
pup treated with axillary RT versus
low-up results presented at the
fences between the two arms with
vs. 81.4% with axillary RT),
ND was 81.7% vs. 78.2% with
% with ALND vs. 4.07%

nodes before preoperative system}

response to preoperative therapy

results of these studies have show

disease prior to preoperative

negative rate when performed afte

SENTINA study,‘ the overall false-negative rate was 14.2%. In thell
ACOSOG-Z1071 trial." the false-negative rate was 12.6% and in the SI
FNAC trial, the false-negative rate was 13.3

‘Subgroup analyses from studies have shown that 1) using dual-agentl

lymphatic mapping (radiotracer and blue dye); 2) identifying three or more]
‘SLNs; and 3) marking the metastatic lymph node with a clip before]
neoadjuvant therapy and then resecting it at the time of surgery reduces}
false-negative rates to <

A subgroup analysis of the ACOSOG Z1071 trial showed lower fals:
negative rates in patients who had a clip placed in the positive Iymphl
nodes at the time of initial biopsy followed by removal of the cl

during SLN surgery after preoperative systemic therapy." A

study of selective localization and removal of

known as targetéd axillary dissect

reduced to approximately 2% com

lipped lymph node alone. "*

142. National
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the time of diagnosis,
positive lymph nodes
El recommends SLN mapping

jeeded in these patients. If SLN is
(data, no further surgery

criteria are met: the patients have
operative systemic therapy. only.

go BCT (BCS + WBRT). If any of
recommends level | and II axillary

al data, no further surgery is
| fiteria are met: the patients have
operative systemic therapy, have
mpectomy or mastectomy along
of undissected

Panel recommends level | and II
Érgoing mastectomy with clinically
| tne Panel notes that axilary
control of disease. Based on the
EN Panel recommends no ALND

core biopsy of suspicious nodes w

According to the NCCN Panel, thal
and Il nodes is limited to patients \
(in those who did not receive preo]
residual disease after preoperati
patients with biopsy-proven axilla
clinically node negative after preof
‘SLNB with removal of the clipped
category 28 recommendation as t
SLN is performed after preoperati

According to the NCCN Panel, bas
rate can be reduced by marking bi
removal, using dual tracer, and byl
(targeted ALND): When sentinel nj
Panel recommends level Lang I
axillary staging.

Radiation Therapy

Principles of Radiation Therapy
itis important to individualize RT pl

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t wall and nodal regions is.
mixed-energy photons With or
ns (DVHs) should be used to
to nommal tissues (ie, heart,
[the intended planning target
st wall, Supraciavicular fossa,

€ and has shown to have a
nized trials have demonstrated
additional boost dose of radiation
am) to the tumor bed. 5." For
lo spare normal tissues using
Invard planning using segments

fractionated WERT
Gy) compared to
The 10-year follow-up
ent with the 10-year results of the
tumor control and. breast

RR OTC Ree ey étui
3.0% in the-40-Gy group. The 9-4
and 93.4% in the 40-Gy group. Ra

disease were comparable betweet

Other shorter schedules of deliver

Gy in 5 fractions once weekly. After 10-year follow-up, there were nol
significant differences reportec effects for the stand:

schedule for 5 w

The FAST Forward trial randomize
cancer (n = 4096) after BCS or mi
In 15 fractions over 3

ith 27 Gy in 5 fractions|
% Cl, 0.51-1.44) and 1
per fraction; HR, 0.67; 959
The moderate or marked tissue effects in the brea
Gy, and 10% with 40 C

K (5.4 Gy
vith 26 Gy in 5 fr

144. National
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fe Panel has defined the target as
commends a dose of 40 to 42.5
ing whole breast radiation
In its équivalence in efficacy and
ypofractionated tials. While
42.5 Gy in 15 to 16 fractions are
À schema for whole breast
regimen of 46 to 50 Gy in 23 to
fatients, The RT boost doses
nce are 10 to 16 Gyin 4to8

| delivered as 5 (once weekly)
iehts with pTis/T1/T2/N0 aged

[ractionaton forthe boost
natively) 26 Gy in 5 daily

‘ed, though data beyond 5 years

bailable for this regimen and

D its use. The Panel also notes

9, it is essential to utlize 3D

exposure to heart and lung.

recommends a dose of 45 to 50.4]
wall. A boost at the scar of 1.8 to
approximately 60 to 66 Gy may bi
ecial consideration should
ensure that the skin dose is adeq

Regional Nodal Irradiation,

‘Two studies, MA.20 and EORTC
regional nodal irradiation (RNI) to
upper axillary nodes including the
WBRT or chest wall irradiation aftg
MA ..20) regional recurrences were
irradiation only to 0.7% with the aq
recurrences were reduced from 1
DFS was seen from 77% t
compared to those who did not.
reduced the incidence of regional
decreased the rate of distant meta
median follow-up of 10,9 years. 1%
that breast cancer mortality (19.89
breast cancer recurrence (27.1%
reduced with internal mammary ar

The independent contribution of in

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50.4 Gy in 25 to 28 fractions to
RT boost can be delivered to

year cumulative incidence of
with WBRT, yielding an

equivalence.** However, given the
yen WBRT and APBI itis not
Jopriately selected patients.

e generally been comparable or
For example, the IMPORT-LOW

irradiation delivered as 40 Gy in

e breast tangents and found le:
jearance, and lower average

NCCN Recommendation for API
ASTRO APBI Consensus statemef
NCCN Panel recommends AP BI 14
meets the ASTRO 2016 "suitable

positive invasive ductal carcinoma
negative margin widths of 22 mm,

and also permits APB! in patients #
low or intermediate-grade DCIS nf

using IMRT),
patients who do not meet the abot

Adjuvant Radiation Therapy After
Those who have a positive lymph
Therefore, after BCS WBRT is str
boost to tumor bed for node-positi
positive nodes; category 2A for th
recommendation is supported by 4
EBCTCG showing reduction in 10}
received WBRT Versus those who}
C1 0.48-0:56). In addition, a sig

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pnd distant recurrence and
C 2292011

ncer mortality with 15-year follow-

port the importance of RNI after

i

i

y of the internal mammary nödes
at controversial due to the

k orean trial KROG 08-06 studied
al mammary nodes after BCS or
randomizing patients to RNI th
internal mammary RT. Radiation

H nificantly improve the DFS in

|. However, there was a

Is with internal mammary nédal

located tumors. '®° Conflicting

Cooperative Group that

ir study on RT to internal

ith positive nodes and early-

o the internal mammary nodes
1,491), while no RT to internal.

specifies the fields that should be
comprehensive RNI. According to
consider risks versus benefit
toxicities, comorbidities of the pati
including RT to the internal mam
planning with normal ti

'RNI After BCS for Node-Negative

tumors who have undergone limit
and also have other risk factors, it
negative disease, or LVI."""
RMAñerBCS for Node-Positive 1
nodes; if a patient meets all of the|
not receive preoperative chemot

inclusion of any portion of the und
strong consideration of comprehey

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tamoxifen for 5 years.
the BCS, radiation, and
moxifen arm. There were no
jectomy,)* These results were
study with’a median follow-up of
significant reduction in IBTR was
BOS and tamoxifen arm
ption and tamoxifen arm. =
pied in other studies of similar
| relapse without RT is relevant
lualized after a discussion of the
itment to 5 years of endocrine

mastectomy radiation. The trial as]
including RNI versus no RNI wher |
mastectomy. Based On the benefi
Panel recommends comprehensid
at risk (category 1 for Tor more pd

Post-Mastectomy RT-for Node-N4
In patients with negative nodes, t
post-mastectomy RT (PMRT) is à
Panel has noted that it may be cor
with high-risk features. Based on ff
patients enrolled onto the RNI trial
patients with the following high-ris
tumors, T3 tumors, or tum:

at least one ofithe following: grade
considered for PMRT with RNI/to i
Features in node-negative tumors
recurrence include primary tumor:
margi

In patients with positive pathologid}
margins is not possible, the Panel

148. National

Comprehensi
NCCN eu

Network

plated to administration of
ative systemic chemotherapy
inical/anatomic stage.
fe preoperative systemic therapy)
(after preoperative systemic
th stage Ill disease
postoperativ ntrol even for patients:
ho have a path
jemotherap

[Those who have clinically negative nodes at diagnosis, that remain
pathologically node-negative at definitive surgery (after systemic therapy),
[should receive adjuvant RT to the whole breast with the addition of boost
[to the tumor bed after SLNB.

fally positive nodes at diagnosis
negative after preoperative
ABP B-51 trial assessing the
lable, the existing
fat presentation is at high risk for
sidered to receive

all levels of the undissected axilla
treatment.

RT After Preoperative Theray
Those who have clinically positive]
preoperative systemic therapy and
strongly considered to receive RT f
RNI with inclusion of any portion d
the discussion above.

For those with positive nodes (yp
axillary dissection is the standard
11202 trial; however, if RT is indic
with comprehensive RNI with inch
axilla at risk

Those who have node-negative dif

preoperative systemic therapy and
axillary node dissection may foreg|

benefit of RT in patients treated wi

]
Two prospective trials are ongoin: |
51/RTOG 1304 [NCTO1872975) al

149. National
Comprehensiv

NCCN Can

Network’

an increased rate of local
lat a median follow-up of 58
lof distant or local recurrence were

ms were compared at
chemotherapy
ctive and

ne therapy either

NCCN Panel, Sequential or
lacceptable. However, due to
rine therapy at the completion of

[el recommends that olaparib be
iA trial 2 olaparib was not
d data on safety of

150. National

Comprehensi
Network'

disease** Coordinating
reconstrüctive surgeon should

ummarized for these patients in
lunder Principles of Breast

tion includes patient preference,
lies, plans for irradiation, and
ction team. Smoking and obesity
ypes of breast reconstruction,

hg and obesity are therefore
breast reconstruction by the

d of increased rates of wound
Liete flap failure among patients

that does not impact the

1
fs associated with an improved

may.be partially
reconstruction with.or without recc

Those undergoing mastectomy sh
options and timing of breast recon

Many factors must be considered
reconstruction” There are several
that include the use of implants, al
Reconstruction with implants ¢
placement ofa permanent subped
subpectoral expander implant folld
implant envelope with stretching of
overtying skin followed by replace
implant. A wide variety of implants
silicone gel, or a combination of sq
silicone envelope.

Autogenous tissue methods of red
fat, muscle, skin, and vasculature
back) that may be brought to the A
(pedicle flap) oras free flaps with à
blood fromthe chest wall/thorax.*

151. National
Comprehens
Can
Network

revision surgery involving the
\d areola reconstruction and

t décisions related to breast

ly increased risk of implant

of an implant. Furthermore, post-

five impact on breast cosmesis

Hiate breast reconstruction, and

radiation when immediate

itologous tissue or breast

lave not found a significant

piter RT.°° The preferred

diated patients was a subject of
e experienced breast cancer
immediate tissue reconstructions
red to precede autologous.

cosmesis, implant exposure, and
hi
is the preferred method of breast

Skin-Sparing Mastectomy
kin-sparing mastectomy procedu
and involve removal of the breast

a composite of autogenous tissue
mastectomy involving preservatior
subject of increased attention. Pod
include improvements in bres
sensation following mastectomy
these QOL issues has not been w|
from surgical series, y
NAC-sparing mastectomy in sele
of occult involvement of the NAC \
recurrence. **22722° NAC-sparing à

152. National
Comprehens
Can
Network

her nipple discharge associated
[suggesting malignant

ues. Several prospective trials
frastectomy infhe setting of
jo
|
L

y procedure include an improved
in the size of the mastectomy
Épecially when autologous tissue

to perform immediate
studies have been performed,
dies have indicated that the risk
patients receiving skin-sparing
indergoing non-skin-sparing
certainly existin the
Kin-sparing procedures. “22s
erformed in a delayed fashion if
poles are devoid of sensation
fing mastectomy should be
ry team that Works in a
ide proper patient selection for
al sequencing of the

The evolving field of oncoplastic si
displacement” techniques perform
mastectomy.

removal of generous regions of br
conform to the segmentally distrib
mastopexy" techniques in which

‘Advantages of oncoplastic volum

permit the removal of larger regior

wider surgical margins around the
preserve the natural shape and ap
breast resections.“

Limitations of oncoplastic volume
standardization among centers, pq

153. National
Comprehensiv

NCCN Can
Network’

lecondary surgery, which could
|lor could require mastectomy with
| procedures can be combined

ed breast to minimize long-term

struction should primarily focus

ment should not be

154. National
Comprehens

NCCN Can

Network’

le, appropriate patient selection
je systemic therapy in a new.

[significant différences in
jotherapy is given before or after
Intage of administering
fo improve surgical outcomes,
inoperable tumors to operable
of patients with operable breast
tion procedures.

[adequate tumor response
[mic therapy to improve the

therapy may provide important
E to therapy. Achieving a

therapy after surgery. It many allow
alone-or allow for limited radiation
becomes clinically node negative 4
addition, preoperative systemic thd
research platform to test novel th
providing tumor specimens and bl
systemic treatment.

Selection of Patients for Preoperal
Not all patients are appropriate car
therapy. According to the NCCN Py
breast tumors, preoperative systen
locally advanced or inoperable bre]
inflammatory breast cancer; those
eN3 regional lymph node nodal dis

In patients with operable tumors, ph
preferred approach for the followin
HER2+ breast cancer that is clinic
node positive; ifthe patient's bre:
high likelihood of response; or if a
tumor is large relative to that of th

155. National
Comprehens
Can
Network

tu disease when the extent of
ptients where the extent of the
hose tumors are not clinically
erative therapy should be made
orative multi-disciplinary team

ive endocrine therapy for
HER2-negative, cNO breast
Idemonstrate a significant

rence Score and clinic

nificantly more likelyıtorrespond

patients with T1/T2,node

H the role of the Recurrence
pr pre-operative systemic therapy.
cores are associated

!
1
I
i
1
[
i
Le chemotherapı

wed the use of 21-gene
to preoperative chemotherapy,
Pote for considering the Use of a

same: eradication or control of un

Endocrine Therapy: Preoperati
to those with strongly HR-positive |
risk luminal biology based on clinid
signatures (until desired effect is 1
ACOSOG 21031 trial show that pr |
effective in reducing residual dise4
with low rates of local-regional “|
|

According to the NCCN Panel, the
aromatase inhibitor (with ovarian
premenopausal patients) or tamo)
premenopausal patients). The prel
postmenopausal patients is an/ard

HER2-Targeted Therapy: For pati
that are candidates for preoperati

156. National
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Network

fzumab to trastuzumab and

[supports the FDA-approved
jegimen may be administered

Il multicenter, double-blind:
¡compared preoperative
Ixorubicin or epirubicin and

her pembrolizumab (n=784) or
Imab or placebo administered
surgery. in patients with

After a median follow-up of 39.1
nt-free survival was seen with the

chemotherapy.
8%, respectivel

ial results showed an.
ted with chemotherapy plus
bo arm (81.3% vs. 72 ith

Response Assessment During P!
The NCCN panel recommends th
assessed by clinical exam during

therapy. Patients with operable br
disease while undergoing preoper
promptly to surgery. Imaging durin
not be done routinely but may be q
suspected. Imaging prior to surged
multidisciplinary team

In-a.multicenter analysis of patient

each breast cancer subtype.”
associated with worse event-free
1:55 t0.2:16 across

As noted under the
method of pathology reporting, th
pathology reporting for all invasiw
breast-Oñ the Principles of Preop|

157. National
Comprehens
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Network

redicted Sensitivity to a particular
| The decision to use systemic

I balancing risk for disease
nagnitude of benefit from
therapy, and comorbidity. The
bration between the health care

Poy
‘ith breast cancer based on their
ts are then further stratified

d on anatomic and pathologic
Le, ALN status, angiolymphatic

sitive, HER2-negative tumors
E tumors, receive adjuvant
rence and those deemed at

and additional adjuvant therapies À
making: Patients with ER-negativ 1
considered for endocrine therapief
group are also limited. The same di
PR should be interpreted as either]
nuclear staining) or negative (if 1
For the purposes of this guideline
referfed to as “hormone receptor ( |

subgroup of ER negative/PR-posi

‘The magnitude of Fisk reduction frq
dependent on level of ER-expresst
gene expression assay test result:
likely to benefit from endocrine the
with endocrine therapy alone vers

|
|
Patients with invasive breast ae
considered for adjuvant endocrine}
lymph node status, of whether adj
administered.” Selected studies

cancers may be less sensitive to $
other studies have failed to confiry

158. National
Comprehens
Can
Network

'ostmenopausal patients.5 Ih
acjuvant tamoxifen decreases the
Ihe annual odds of death by 31%
patient age, menopausal status,
Ih tamoxifen and chemotherapy,
pwed by sequential tamoxifen."
lonstrated that 5 years of

fears of tamoxifen, 2992

and postmenopausal patie!
pxifen. The outcome analyses of
bnowed that by extending adjuvant
and breast cancer-related
urrence during years 5 to 14 was
jersus 25.1% for controls (absolute
lo received tamoxifen for 10 years
ion, possibly due to a “carryover

e was 0.90 (95% CI, 0.79-1.02)

t and 0.75 (0 ) after 10
ps in the incidence of contralateral
iced mortality was also apparent

with tamoxifen: With regards to
Ets noted in all patients in the

cancer. These studies have utiliz
Sequential therapy following 2 to

therapy following 4:5 to 6 years of
treatment of patients with functior

patients whose ovarian function c}
treatment-induced amenorrhea

The results from two prospective,

evidence of an OS benefit for pati
receiving initial endocrine therapy]
anastrozole (HR, 0.53; 95% Cl, Of

0.83; 95% Cl, 0.69-1.00: |

disease)) when compared with ta
therapy. In addition, the NCI
survival advantage with extended]
placebo in patients with ALN-posi
ER-positive breast cancer Tan
different side effect profiles, Both
sweats and may causé vaginal dı

159. National
Comprehens
Can
Network

Étients in the combined tamoxifen

over those in the tamoxifen

effect from the weak estrogenic

complete elimination of

al sub-protocols show a lesser

xifen'on endometrial tissue:

fen on quality of life, with most
not significantly

BI density with anastrozole;291

lastrozole in the presence of

Ino evidence for an interaction

use of tamoxifen alone for 5
xifen for 2 years followed
trozole for 2 years followed

early analysis compared

heluding those patients in the

lof treatment only.°° With 8010

hs superior in the letrozole-treated

bg rank P = 1003)" No interaction
observed. No difference-in OS

Jovascular side effects in the

noted with either tamoxifen fol
as compared with letrozole alone
1.05; 99% C1>0,84=1.3:

99% CI, 0.76-1.21),°7

Five tials have studied the use of
equentilly by a third-generation
postmenopausal patients. The tal
randomized 426 postmenopausal
completed 2 to 3 years of tamoxitd
switch to anastrozole to complete
therapy.” The HR for relapse st
anastrozole (HR, 0.35; 95% Cl, 0.
fewer deaths (P = .10).” U
relapse-free survival as 0.56 (95%
analysis remained at 0.1. The 14
postmenopausal patents wit bre]
2 to 3 years of tamoxifen to either
exemestane to complete a total off
]
1
|
1

results at a median of 55.7 month:
superiority of sequential exemest
0.88; P=-0001)with a significant
ER positive tumors (HR, 0.83

160. National

Comprehensi
Incen] Can
Network

DS (HR, 0.53; 95% Cl; 0.28-0.99;
18, ARNO 95, and ITA studies
IR, 0.71; 95% Cl, 0.52-0.98; P=

Ixemestane alone versus
b 3.0 yearsfollowed by
one therapy.*'* At the end of 5!
kıroup versus 86% in the
IR, 0.97; 95% Cl, 0.88-1.08; P
the BIG 1-98 trial, in which
/erse sequence of letrozolé
Id with significant differences in

ferences in terms of efficacy or
ozole, letrozole, and exemestane.

In two randomized trials (TEXT ar
HR-positive early-stage breast cal
(exemestane) plus OFS or tamox]
‘Suppression of ovarian estrogen

GnRH agonist triptorelin, cophore|
was 92.8% in the exemestane plu
tamoxifen plus OFS (HR for recur
001)*1 The OS did not differ sig

ath in the exemestane plus OF:
37).

A 3-year median follow-up anal
sustained improvements in DFS

tamoxifen plus OFS (HR- 0.77. 9
recurrence-free interval but not Os
Ultimately, With longer follow-up (
demonstrated for OFS + exemest
recurrence, but not in exemestan|
relapse not receiving chemotheraj

The benefit of OFS in premenopal
vas also seen in the results of th

161. National

Comprehensi
Incen] Can
Network

hded for a minimum of 5 years. A
rd University studied risk of
years of endocrine therapy» i#

bf recurrence between years 5

al 5 years of endocrine therapy.”

lof extended endocrine therapy in

love}! and the aTTom trial
ind death from breast cancer with

noxifen, there is evidence for
e therapy from several
lin

letrozole in patients who had rece
followed by no endocrine therapy
quality-of-life analysis demonstrat
life during extended endocrine th
‘ongoing menopausal symptoms al
data are available regarding
years or long-term toxic effects fre
ATLAS trial data do not provide cl
postmenopausal patients.*** Ther
an Al for 5 years is better for long

In the extension study of ABCSG
patients received 5 years of adjuv
years of anastrozole or no further
months, patients who received an
have a statistically significantly res
patients who re

0.40-0.96; P = .031).*

162. National
Comprehens
Can
Network

10 had completed 45 to.6 years
ion of prior tamoxifen of 5

Vs! 0.21%; HR

ith respect to OS.
% Vs. 14%), fractures

Adjuvant Endocrine Therapy for A
premenopausal at diagnosis, the
tamoxifen alone (category 1) or ta
plus Al for 5 years (category 1). P
diagnosis and who become amen
continued estrogen production fro
Menopausal stat

stimulate ovarian function. To as:
assessment of circulating LH, FSI
considering this subset for Al thet
estradiol and. FSH/LH levels shoul

After 5 years of initial endocrine t
postmenopausal at that time (incl
postmenopausal during the 5 year
Panel recommends considering/e>

Additional considerations during 4
management for patients on adjuv
ent of hot f E

163. National
Comprehens
Can
Network

ated as intermediate
spectively. The mild CYP2D6
im, sertraline, and venlafaxine
on tamoxifen metabolism. °°°.5°

a large retrospective study of
recurrence was significantly

YP2D6 genotype in a Subset of
responsive, early invasive breast
jetween CYP2D6 allelic status and
llelic status and tamoxifen-related
the ATAC trial found no

mes.
the NCCN Breast
P20 testing as a tool to determine
| This recommendation is
eribing a selective
reasonable to avoid potent and
{particularly paroxetine and

ists,

ecologic Screening is

treated with bisphos
examination with preventive denti
should take supplemental calcium

The incremental benefit of adding)
therapy in patients with low clinica
Verysmall, low.grade, lymph nod
The decision whether or not to ad
patients with HR-positive, HER2+
factors including lymph node st
age, comorbid conditions and/or tf
testusing multigene assays.

Several commercially-available gd
determining prognosis by predictit
or survival. Of these, only one, th
been clinically validated for predi
‘chemotherapy to further reduce tl

164. National
Compre
Cancer
Network

node-negative, HR-Positive-
| 0-10, ne risk of distant
Le no incremental benefit from
endocrine therapy.202552 At the

ymph hodé-negative,

f high RS (2 31) have a higher
[analyses of prospective studies
t chemotherapy.2625:

d similar disease-free
'eived adjuvant chemotherapy
with endocrine therapy alone.
O years of age or younger with
urrence with the-addition of
rapy.="' The cutoff for low
n TAILOR versus NSABP B-20.
late the 21-gene assay both as a
d identified RS cut-offs to predict
patients with node-negative,

(1-3 positive lymph nodes) and a 14
chemotherapyis likely to be very 4

There is a clear benefit from adjuv
positive, HR-positive, HER2-negat
secondary analysis of the SWOG
lymph node-positive tumors, high
chemotherapy benefit: This study
node-positive, HR-positive postm
to endocrine therapy with tamoxif
followed by tamoxifen.**° Compara
CAF among patients with a high R]
DES (55% vs. 43%; HR 0.59, 95%|
HR 0.56, 95% Cl 0.31-1.02).*

165. National
Comprehens
Can
Network

renee By.
| assessments received

fesults (Le. either high clinical
igh genomic risk) were

br the no-chemotherapy group on

genomicesult. The primary

pmonstration that among those
e 5-year rate of survival without
le adjuvant chemotherapy was

lg patients at high clinical riskAüw,
year rate of survival with no
chemotherapy was 95.9% (95%
2.3 to 95.9) in those who did not
fastasis or death with
3% Cl, 0.50 to 1.21).*** Among
risk, 5-year survival with no
6)
191.8 to 97.0%) without
is or death with
% Cl, 0.59 to 2.28). Th
ne signature do not provide
E nemotherapy

chemotherapy versus 95.6 (95%
receive adjuvant chemotherapy.
benefit of adjuvant chemotherapy
genomic risk is likely to.be small.

50-gene assay (PAMS0): The 504
(ROR) score stratifies patients wit 1
medium, añd low risk groups. Sev
prognostic value of ROR score in

In.a study from the Danish Ay
patients with lymph node node-ne|
distant recurrence risk of 5.0% es
with high ROR had a distant recur
22.0%)"%)-Based.on these anal) ÿ
HR-positivé) HER2- negative, Iymi
in the low range, regardless of tun
same prognostic category as thos

In patients with 1-3 lymph-node pq
disease with low-risk of recurrenc
less than 3.5% at 10 years with
study, no distant recurrence v

166. National
Comprehens
Can
Network

trials- ABCSG-6 and ABCSG-8,
and lymph-node node-negative
ne assay had risk of distant

independent of conventional
1 and T2 HR-positive
tumors, a 12-gene low-risk

nor into the same prognostic

sitive nodes in the low-risk group
[0 years,*** suggesting that
in these patients.

[index (BCI) is a combination of

ression ratio (H:l ratio) and the
Ih clinical prognostic factors

mph node status), the HI ratio

ay In a
was prognostic in node negative
nd late (years 5-10) distant

apy and ability to deten
distant recurrence, the NCCN Pan
implications based on risk scores

;
Multigene Assays for Axillary Lymp
HER2-Negative Tumors |

}

‘Small tumors (up to 0.5 cm in greal
Iymph nodes have a favorable prog
recommended. A 4
may be considered in this group ol |
contralateral breast cancer, as wel
of local/regional and distant recurrd

For patients with invasive ductal or
diameter and no lymph node invoN
NCCN panel recommends strongly
assay to help estimate likelihood o
chemotherapy (category 1). The p
analysis from the TAILORx study. #
considered in patients 50 years of
16-25-Also, patients with T1b turn
considered for endocrine monothel

167. National
Comprehens
Can
Network

mes with of without
al risk/high genomic risk group
gene panel is not useful guiding
[subgroup of patients

be concordant with each other
led head-to-head prospectively,
failable assays for a specific

NM HR- Positive,
N the panel recommends
by endocrine therapy (category

ith pN'1mi andlless than or
pre most often candidates for

with. Ntmi and NT tumors, while
to be predictive for adjuvant chem
and can be used to identity low-ri
or no absolute benefit from adit
endocrine therapy. A secondary al
trial using the 21-gene assay dem
for patients with 1-3 involved axila
significant benefit for the addition q
high-RS (2 31) The phase III R
demonstrated that for premenopal
positive, HER2-negative, node-po}
Recufrence Scores up to 25 had |
chemotherapy to endocrine theraf
survival .* In the MINDACT trial
Who hada high clinical risk of rec
assay, the rates of survival were
adjuvant chemotherapy in additio
those received adjuvant endocring
chemotherapy could be omitted in
have not proven to be predictive o

For those who are candidates for

168. National
Compre
Cancer
Network

negative, high-risk breast
lly involved lymph nodes
éthologically involved

ppy in HR-positive: HER2-
benefit of adding palbociclib to
sive disease-free survival.°7°?"

ed after a median follow-up of
fant improvement (3.3%) in

.003).) for stage Il and
7 Additional follow-up

2-negative, high-risk breast
Égory 1, preferred option for this

adjuvant chemotherapy or residual
a clinical stage, pathologic stage,
score 23 (category 2A)

Adjuvant olaparib may be used cı
In patients eligible for both adjuva
sequencing is not known. (For se
with RT, see BINV-I on nccn.org)

Adjuvant bisphosphonate therap)

management of osteoporc
metastases.

Bisphosphonates: In the Austrian

Group trial-12 (ABCSG-12) trial, fq
significantly reduced the risk of re
the risk of death by 49% (HR, 0.5:
was seen in either DFS or OS in t
under 40 years” In a planned su
Zoledronic acid improved DFS in 1

169. ES

National
Comprehensi
Can

Network

fe therapy, the greatest improvement
33, P = .004) and bone fractures

En on distant recurrence outside
Enopausal patients, bisphosphonate
kant effect on bone recurrence.
zoledronic acid significantly

15%, RR=0:73; 99% Cl 0.53 to 1.00)
ty was not statistically significant

19 to 1.11)”

1e ABCSG-18 trial studied thejeffect
lents treated with adjuvant Als and
(HR 0.5, P< 0001), whichwas the

final analysis after a median follow-
efit with denosumab. Adjuvant
[s-free survival (88.9vs. 86.4%; HR,
0.9 vs. 89.9%: HR, 0.80; 95% Cl,
[the phase 11! trial (D-Care) tral failed
etastasis-free survival in those

phase Ill trials, denosumab is
want setting.*”* The panel

Preferred Regimens

Regimens listed as preferred in}
cyclophosphamide (AC) follow
or biweekly; docetaxel plus cyc!
BRCA 1/2 mutations; pembroli

capecitabine for residual ER: di

Meta-analysis from Early Bread
(EBCTCG) has shown that ant
chemotherapy reduces the risk|
no chemotherapy. The use of d
reduce the risk of breast cance
mortality. °°"

The results of two randomized
without sequential paclitaxel ch]
node-positive breast Cancer sug
results from one of the trials shy
addition of paclitaxel.*

advantage of the paclitaxel-con]
with ER-negative breast cancer

170. National
Comprehens
Can
Network

jek schedule or a weekly
Fnparisons, weekly pacitaxel was
[FS (HR, 1.27: 95% Cl, 1.03-1.57.
2-1.72/P = 01), and
y-3-week paclitaxel in DF:

ut not in’ OS.® Based on these
CALGB trial'9741 that showed
Very 2 weeks to have a survival

of AC followed by every-3-week
I regimen has been removed from

chemotherapy in a trial that
p Ill breast cancer.** Ata median
75%; HR, 0.74; 95%.Cl,0.56
IR, 0.69; 95% Cl, 0.50-0.97;
compared with AC. Non-
ich as TC may be preferred

flemic therapy indicates higher risk
o X, a multicenter open-
d the efficacy and safety of.

therapy option for those with TNE
preoperative therapy. For those w
TNBC, according to the NCCN pal
(discussed in section adjuvant th
disease) adjuvant olaparib for 1 |
pN1 disease after adjuvant chem
after preoperative chemotherapy
did not receive capecitabine; thus
guide selection of one agent over|
capecitabine or Olaparib with RT,

If pembrolizumab was given in cof
preoperative setting, based on the
recommends adjuvant pembroliz

Other Recommended Regimens

Other recommended regimens inf
epirubicin and cyclophosphamide|
cyclophosphamide (TAC): paciita
and docetaxel+ carboplatin. |

À trial compared 2 dose levels of

171. a

National
Comprehensive
Cancer
Network

C and 68% with FAC (HR, 0.72;
5 87% with TAC and 81% with
1008). DFS favored TAC in both

73 months,

when compared.
001) and OS (HR, 0183;
en AC followed by T was
[9 non-inferiority compared with

lé dose dense AC; AC every 3
weekly paclitaxel; and
TNBC after adjuvant

chemotherapy.°°*22° No benefit fro
or cyclophosphamide was sh
versus no chemotherapy have shi
chemotherapy.

Results of a randomized trial in pa
standard adjuvant chemotherapy
with low-dose capecitabine (dose
year) improved 5-year DFS
receive adjuvant low-dose capecit
in those who did not (HR for risk à
Cl, 0:38-0.92]; P=.02), the
capecitabine was 85.5% versus 8
0.47-1.19], P= .22).%°

‘Adjuvant Therapy for HER2-posit
Trastuzumab containing chemothg
HER2-targeted therapy are abacı
HER2-positive disease:

The panel recommends HER2-tar
HER2-positive tumors (see Princi
Guidelines for Breast Cancer).

172. National

Comprehensi
NCCN eu

Network

tumors of the same size:

and 10-year recurrence-free
Y, in patients with tumors
tive tumors, and 70% and 61%,
je, ER-negative tumors. Two
urrence-free survival in this
'egative tumors measuring 0.6 to
ithout trastuzumab. In the first
ites of 7.1% and 93.7% (P <
ositive and HER2-negative
| with no recurrence-free survival
foup when hormonal receptor
[rospective study of patients with
ecurrence at 5 years was low
Pgative disease and 92% [95% Cl;
P' Subgroup analyses from several
istent benefit of trastuzumab

tuzumab'as an option for
je 1 tumors, based on a trial of.

[sos patients
his combination. The 3-year rate of DFS was 98.7% (95% Cl, 97.
land the risk of serious toxic effects with this regimen was low (incidence of

9.8)

The BCIRG 006 study randomize
node-positive; or high-risk node-

docetaxel; AC followed by docetal
carboplatin, docetaxel, and trastu
follow-up, patients receiving AC fq
(AC-TH) had an HR for DFS of 0.

group of patients inthe control an
regimen without trastuzumab (AC
when patients in the carboplatin/d
arm were compared to patients i)
significant difference in the HR fo
trastuzumab-containing arms. An
in both trastuzumab-containing a

AC-TH vs, AC-T = 0.63; P= 0017
Cafiac toxicity was significantly i
>10% relative decline in left ventri
the AC-TH arm (186%;P </000}
AC-TH than TCH (2% VS,0.4%: A]
clinical event revealed more dista]
(144 vs. 124) but fewer cardiac ey
vs, 21) In the FinHer tal, 1014

vinorelbine followed by 3 cycles of

173. National
Comprehensi

NCCN Can

Network’

[compar on of the two arms (ie;
ab) demonstrated that the HRs

‘astuzumab plus pertuzumab with
with standard adjuvant
ive or high-risk node-negative
ly demonstrated that
y improved 3-year ¡DFS (HR
long-term (8-year) follow-up, the
pr invasive DFS benefit favoring
sive DFS of 86%
) with no OS difference; no
! ibgroup.“ These updated results
| the long-term benefit of adding
erapy for node positive disease
mab with chemotherapy as a
positive tumors > 1 cm. and

toxic than paciitaxel/Trastuzumab.
who received 1 yearof adjuvant T}
trastuzumab/padiitaxel (n = 114) 4
survival rate with T-DM1 of 97,0%
recurrence-free interval of 98.3%
OS rate of 97.8% (95% Cl, 96.344
to evaluate the effica

S not powered]
>, among tho
elved it, the reported 5-year invasive disease-free survi

combination v % (95% Cl: 86.0-96.9%), 5-year recurrence freell
interv 3 2%) and 5-year O (95%
Ci: 95.2-100%).*"" Based on thes

altemative for these patient

Other recommended regimens
Anthracycline followed bytaxane-
used in the NSABP trial B-31,"° N

In the NOAH tral, patients were gl
anthracycline, then taxane alone f
methotrexate-fuorouraci.* in th
docetaxel or vinorelbine before an]

174. ES

National
Comprehensive
Cancer
Network

% (4.9 to 7.8:
5% (5.0to 8.0; P

to incorporate pertuzumab into

igh pCR rates after treatment

nab and pertuzumab (67%) and
jab and pertuzumab (68%).*
ining regimen experienced more

sults, considering the added
lens the panel has added non-
fastuzumab and pertuzumab as

Ing regimen as other

83) primarily in the sı
15% CI0:43-0.83, P = .063). Ner
severe diarrhea:

Based on the trials din the sey
and the above data from ExteNE'
regimens have been induded'as
Docetaxel + cyclophosphamide +
+ trastuzumab followed by paciita
ed ); AC followed by paclite
various schedules); Paclitaxel + tr
neratinib and adjuvant T-DM1

Therapeutic duration and Other C4
targeted therapy

The length of trastuzumab adminis
listed above is 12 months, The HE]
benefit extending trastuzumab to

With respect to a duration less tha
PERSEPHONE trial Showed non-
of trastuzumab treatment, “°° Howe
events in the 6 month cohort comp

175. ES

National
Comprehensi
Can

Network

updated APHINITY trial data, the
fed with trastuzumab in those with

ved in patients treated with
kycline and taxane-based
heted agents are associated with
7, The panel recommends

tion (LVEF) prior to and during

F assessment during adjuvant
[FDA label recommends LVEF
zumab and every 3 months during

proved biosimilar is an
rastuzumab and hyaluronidase*
Is Use may be substituted for
to note that it has a different
Nintravenous trastuzumab.

ple Histologies
Ent recommendations for the
Incers (including pure tubular and

The vast majority of pure tubular,
breast cancers are both ER-posit]
associated with favorable progno:
not be high grade, should be purd
excision, not core biopsy alone),

pathologic or clinical features are

The pathology evaluation and ac
determination: should be reviewe

HER2-positive, or if a tumor with

1.27 Should'a breast cancer be hi
mucinous breast cancer and be ¢|
should be treated according to the
ER-negative breast cancers. The|
data regarding systemic adjuvant}
histologies are lack

176. National
Comprehens
Can
Network

ter BCS followed by radiation, the
losing Wisely” list of

he recommendations state that

te frequency for surveillance of

IS and RT withino’elear.

ptients should wait 6 to 12 months

ry. The routine performance of
not included in the guidelines.
ce to support the use of “tumor
Jone scans, CT scans, MRI scans,
h the asymptomatic patient.

to palliate recurrent disease and

The Panel recommends that patiel
adjuvant tamoxifen should have yq
rapid evaluation of any vaginal spq
risk of tamoxifen-associated endo
patient

Ultrasonography in the asymptom4
test has demonstrated utilty as a
patients, The vast majority of pati q

1
treatment, baseline levels of estral

monitoring of these hormones shi
with an Al is initiated.*" Bilateral

status in young patients with thera
considered priorto initiating thera

‘Symptom management for patient]
requires treatment of hot flashes a
depress

(SNRI), has been studied and is al
flashes. There is evidence sı

tamoxifen with certain selective si

177. National
Comprehens
Can
Network

Erstanding by the patient of the
tration of the medication.*°’ The
bf simple strategies to enhance
[such as direct questioning of the
lear explanations on the value
therapeutic importance of longer

after treatment for breast
risk of lymphedema include
in, infection, and patient
lucating the patients on
and referring for lymphedema

ncer maintain orregain
1 for breast cancer. For these
e use of hormonal birth control
the tumor. Alternative birth
hing intrauterine devices, barrier
future pregnancy, tubal igation or
ine or chemotherapy treatment is

u OTERO pige
cancer is discouraged. The use of]
preferre

study, ABCSG12, demonstrated in
zoledronic acid in premenopausal
with ovarian suppression." Use

in other subgroups remains contr
significantly reduce fracture

adjuvant therapy Als, and improve

mineral density, response to thera
loss or fracture. Patients treated w
dental examination with preventivg
therapy, and should take supplem|

179. National
Comprehensi
Can

Network

ES

he scan, and radiographs of any
fui or appear abnormal. on bone
h or without diagnostic CT of the
biopsy documentation of first
¡generally discourages the use of
I the evaluation of patients with
ce (mostly from retrospective
fanning to guide treatment
tent of disease in select patients
9450 In general, the
Inder-evaluate the lungs and the
lagnostic CT scans. The Panel
pus sites to be more likely than
pging information in this patient

pt FOG-PETICT is optional and

assays may be falsely negative or
discordance between the primary
reasons for the discordance may

differential effect of prior treatment
or imperfect accuracy and reprodu
between the receptor status of pri

3.4% to 60% for ER-negative to El
to ER-negative: and 0.7% to 11%

The NCCN Panel recommends th
recurrent disease be performed,

previously unknown, originally ne:
patients with clinical courses cons]
with prior positive HR results; the
endocrine therapy is reasonable,

is repeated or the result of the mo}

Genetic counseling is recommend
high r

180. National
Comprehens
Can
Network

RT.

Ence pattems in patients with
ctomy and adjuvant

urrence
cular lymph nodes.*** The
ppulation of patients experiencing
[analyses of a combined database

my in patients with stage | and
8%) patients experiencing a:local:
ximately equally divided between
ind those who had received
ment for breast cancer. Of those
to. undergo RT withior without,
urrence. No difference in survival
ment after initial treatment
approximately 50% of both

my-treated patients should
currence (ifit can be

]
its use is discouraged.

of repeat SLNB after mastectomy
The consensus recommendation
recurrence following breast-consel
and a level /Il axillary dissection

The results of the CALOR trial fouf
patients with isolated locoregional |
improves both DFS and OS. Af
overall DFS was 69% in the chem
that did not receive chemotherapy}
all patients in the study was also 4
(88% ys, 76%, P = .024):1 The bl
mostly seen in patients with /ER-n
ER-negative disease, 5-year DFS
Cl, 0.14-0.73) and in those ER-p
versus 69% (HR, 0.94; 95% Cl, 0.
received endocrine therapy.

According to the NCCN Panel, aft
Tecurrences only should be consi

181. National

Comprehensiv
NCCN eu

Network

From the time of diagnosis of recurrent/stage IV metastatic disease]
[patients should be offered appropriate supportive care and]
Isymptom-related interventions as a routine part of their care ÍNCCN|
recognizes the importance of clinical trials and encourages participation
when applicable and available.

je
jended by the NCCN Panel for
dan intact primary tumor is
Jurgery after initial systemic
symptoms or with impending
feeding, fungation, and pain.
faken only if complete local
other sites of disease are not
RT may be considered instead
ollaboration between the breast
to provide optimal cancer control

| survival benefit from complete
patients with metastatic breast
b exist in all of these studies and

essed whether or not surgery on
ary for patients who are
cancer. In the firs
rial, patients ( metastatic breast cancer]
who achieved a partial or complete response to anthracycline-basedl|
emotherapy were randomly assigned to either surgery of the primary
ftumor plus adjuvant radiation or no locoregional treatment.” Ther

ho difference in the OS between the group that re
[group that did not (19. 0.5 months; HR, 1.04; 95% Cl, 0.
In a separate multicenter prospective registry study patients
to first-line syste ere randomized
rimary tumor by
showed no difference in OS between the

local management (mastectomy, or BCS with radiation) followed byl|
systemic therapy versus systemic therapy only observed a benefit with]
surgery.*” While no difference in survival was seen at 36 months, at 40]

in survival with locoregional treatment (46.4% vs. 26.4%;

Cl, 0.49-0.88). The design of this trial is different from the other, the frst]

difference being the inclusion of two prospective studies described abovel

in which patients were included only if they had experienced a response to]

systemic therapy. Second, randomization in the Turkish trial was not]

balanced. Patients who received surgery had lower rates of triple-negative]
isease (7% vs. 17%), visceral metastases ( ) a

solitary bone metastases only (33% vs. 20%).”° In an unplanned]

subgroup analysis, patients who appeared to MN the greatest OS]

benefit from local management included those with HR-positive disease]

(HR, 0.63; 95% CI, 0440.89; P =

disease (HR, 0.64; 95%

0.57; 95% CI 0 38-0.8

182. National
Comprehensi

NCCN Can

Network’

recurrence or stage IV disease
is not curative. Theréfore,

ty are preferred. Thus, the us
preferred to the use of cytot

Ice for treatment of patients with

[cluded the N Guidelines for

cancer at diagnosis are initially
ses are present. These two
Jony metastases) are then further

metastases include pain, decreased
reased QC tal-related,
which are defined as the need for radiation or surgery to
, pathologic fractures, spinal cord on, and hypercalcemia of

It with a bone-modifying agent
denosumab (category 1) in
if bone metastasis is

development of ON include admi
corticosteroids and poor oral hygi
abscess.”

Bisphosphonates
There are extensive data from ran
bisphosphonates for patients with
randomized clinical trial data inclui
pamidronate inthe United States 4
European countries.*°" In meta
treatment is associated with fewer}
less need for RT and surgery to tr

The use of bisphosphonates in m
measure. No impact on OS has bq
bisphosphonates.

The data indicate that zolédronic 4
3-10 4week schedule in conjunct
endocrine therapy, chemotherapy
Three randomized trials have com]
weeks versus every 12 weeks.
among patients with breast cance

183. National
Comprehens
Can
Network

lccompanied by calcium and
es of calcium of 1200 to 1500 mg
Ihendes agents for use in the
ravenousiy over 2 hours or
[15 minutes: The original studies
however, there are limited

can continue beyond that

jonitoring of serum

trial results
p to 2 years. Longer durations of

|
[
| dose and dose reduction or
I
itional benefit, but this has not

bone who are candidates for

‘Systemic Therapy for Stage IV or
HER2-Negative Breast Cancer

Patients with stage IV or recurrent}
HER2-negative tumors with no vis
therapy alone or endocrine therap|
Patients whose disease progress
endocrine-based therapy and thos
IVimetastalic breast cancer are eli

Many premenopausal and postme]
breast cancer benefit from sequer
disease progression. Therefore, pl
disease responds to an endocrine
the tumor or long-term disea:
receive additional endocrine theral
progression on or w
therapy or for di
metastatic disease, patients are ef
ither as monotherapy or in combi
optimal sequence for endocrine th
would depend on previous toleran}

Many trials in HR-positive patients
patients: The NCCN Panel recomy

184. National

Comprehensiv
NCCN eu

Network

vas studied in a phase III study
666) with metastatic,

ler who had not received prior

provement in PFS (24:8 vs. 14.5

\d objective response rate (ORR:

Étion of palbociclib and letrozole

13 and 4 adverse effects seen with

ble included neutropenia (66.5%
la (5.4% vs. 1.8%) and fatigue

las also studied as firstline

pausal patients (n = 668) with

pe IV breast cancer. At a median
tin PFS (25.3 vs. 16.0 months;

B% Cl, 0.45-0.70) and improved

Iciclib plus letrozole compared

events were more common

enia (62% vs. 1.2%)

0 included diarrhea (9.5% v

patients on ovarian suppression.
MONALEESA-7 trial, 672 pre- or
HR-positive, HER2-negative adval
assigned to firstline treatment wi
plus either a nonsteroidal Al or tan
seen with the addition of ribociclib
0,55; 95% Cl, 0.40.69).

At 35 years, an improvementin
46%; HR, 0.71; 95% Cl, 0.54-0.94
reported in> 10% of patients in eit
4%) and leukopenia (14% vs. 1%)}

Based on the above data, the NC

vith CDK 4/6 inhibitors as a categy
postmenopausal patients and prey
ablation/suppression with HR-pos|
breast cancer.

185. National

Comprehensiv
NCCN eu

Network

do be longer in the
months vs. 48.4 months; HR;

| postmeriopauisal patients with
npared fulvestrant 500 mg every
imonthiy versus fulvestrant 250

the tuvestrant 500 mg regimen

* indicating an increased
of fulvestrant. The final analyses
(4.1 months) and reduced risk of
pared with 250 mg Median OS
[95% Cl, 0.69-0.96; P= .02),°

ON) of first-line treatment with
endocrine therapy-naive patients:
ir, demonstrated improved PFS

19) over anastrozole at a median.
honths; HR for progression or
Ihe QOL outcomes were similar
bmmon adverse effects being
(11% vs. 10%) for fulvestrant

In the phase Ill trial, MONALEESA-3, inj
[patients (n = 726) with advanced HR-positive breast cancer who had no]
rior endocrine therapy or had disease progression on prior therapy, the

(combination of ribociclib with fulvestrant showed improved PFS versus]
ulvestrant alone (21 vs. 13 months; HR, 0.5 0.48-0.73).% The}
PES benefits MIN consistent across patients with and without prior]
lendocrine treatment. In a subsequent analysis, a significant improveme
1.97 At 42 months the estimated OS was 57.8% (95%
15.9% (95% Cl, 36.9-54.5) in

mparison
settings studying combination of fuiv
have shown statistically signi
results of the MONALEESA-:

ss multiple trials, including those in the second-line|
trant with palbociclib or a

ablation/suppression
breast cancer

Fulvestrant + Nonsteroidal Al: The
as first-line treatment in postmeno}
metastatic breast cancer has beer
single-agent anastrozole versus al

In one study (FACT), combination
superior to single-agent anastroz

Cl, 0.81-1.20; P= 91)" Ina se
fulvestrant alone or in combination
studied in patients with advanced
to a nonsteroidal Al.° An Al had
18% of patients for a median of

186. NCCN

needed to

National
Comprehensi
Can

Network

Jere superior with combination
up analysis in this trial suggested
kifen experienced the greatest OS
led with monotherapy (median,

ly; HR/0.73; 95% Cl, 0.58-

in the above trialsisot very
fad slightly diferent patient
patients with no prior endocrine
Mic disease) in the SWOG 50226
FACT trial included a more
fropausal and postmenopausal

F The SoFEA trial
crine resistance (who had

ing an Al). Further studies are

fulvestrant as first-line therapy
based on the above data.

‘ost menopausal patients there is
first-line therapy for their recurrent

significant differences in PFS or

NCCN recommendations for first.
patients with HR-positive, HER2-

cancer, NCCN category 1, preferred regimens include a cya

kinase 4/6 inhibitor with an Al: fulve

inhibitor; and fulve

preferred regimen i (ie, anastrozole, letrozole}
steroidal Al (exemestane), and selective ER modulator (tamoxifen or
toremifene). For premenopausal pf

includes ovarian suppression/abla

for postmenopausal patients or al

Preferred Regimens for S f Therapy fe

HR Positive, HER2-Ne
Fulvestrant-Containing Regimens

Second and Subsequent Lines
ative Bre

Fulvestrant + CDK 4/6 Inhibitors:
416 inhibitor may be offered to pati
progression during prior reatmer
chemotherapy (Category 1), beca!
fulvestrant alone in a phase III trial
notes that treatment should be lim

187. National

Comprehensi
NCCN eu

Network

E mainly confined to neutropenia

d an improve
months: HR, 0.

In those receiving abemaciclib and fulvestrant (48% vs. 21%).% In

laddition, an improvement w ith abemaciclib plus
fulvestrant compared with fulvestrant alone (46.7 vs. 37.3 months; HR,

tion of a CDK 4/6 inhibitor to

inhibitor as a category.
d premenopausal patients with
sitive HER2- negative,
nel notes that if there is disease
jerapy, there are limited data to
another CDK 4/6

fulvestrant vs. 13.1 months for an:
P="0496)."°' This study used ah
weeks for 3 doses and then 500 n
observed to be longer in the fulve:
group (54.1 months vs, 48.4 mont

A phase Il study of fulvestrant in
breast cancer-and dise:

partial response rate of 14.3% wit
achieving stable di

of exemestane versus fulvestrant
postmenopausal patients with HR}
experienced disease progression
comparable (32.2% vs. 31.5%; P
administered as a 500 mg loading]
day 14, day 28, and then monthly.

Fulvestrant Plus Alpelisib: In à ran
572) with advanced HR¢positive bt
status had received a prior Al eith
Patients were enrolled into either

188. National

Comprehensi
Incen] Can
Network

remained significantly longer with
placebo plus exemestane at 11.0

lus Ende

e efficacy of tamoxifen alone
us, an oral inhibitor of mTOR, in

metastatic breast cancer

edian follow-up of 13 months, an
linical benefit was 42.1% (95%
161 1% (95% Cl, 46,9-74:1) with
fent in median time to progression

ith tamoxifen compared with

Bion was 4.5 months (95% Cl
months (95% Cl, 6.01-13.9) with

ents with advanced, HR-positive

‘apy for advanced disease,
without the MTOR inhibitor
tween the treatment arms (HR,

0.38; 95% Cl, 0:31-0:48; P < .000
that occurred more frequently in th
stomatitis, infections, rash, pneu]

on-treatment deaths." Based on
the NCCN Panel has included eve]
for patients who fulfil the entry crit
fulvestrant in combination w 1
while on an everolmus-contanino}
an additional line'of therapy with a

Aromatase Inhibito!
therapy. The three Als (änastrozoll
shown similar efficacy in the seco
maybe be useful in patients desiri
not received-an Alas firstine tre
combination therapy. Patients wh«

189. National

Comprehensi
Incen] Can
Network

recurrent/stage IV breast
[clude fulvestrant with a CDK 4/6

with alpelisib; everolimus with
pnotherapy with fulvestrant,
Étrogen receptor 1 (ESR1)

ted in patients with prior exposure
lgenerally resistant to both Als and
tions retain sensitivity to

E of the following to fulvestrant: a
lor alpelisib, if the tumor has

es for Ther Positive,
\drogens such as
aciclib have been listed as

H the activity of abemacicib as a
factory HR-positive,
ho had disease progression

i
|
|
feceived multiple systemic.

included single-agent abemaciclib|
progression on prior endocrine the
metastatic setting.

‘Systemic Therapy for Stage IV or
Breast Cancer

For patients with HER2-positive,
Cancer, the treatment approach is
with systemic chemotherapy \The
FDA-approved biosimilar is an ep}
Also, trastuzumab and hyaluronidg
may be substituted for trastuzumal
différent dosage and administratiof
trastuzumab. Doses and schedule|
HER2-positive metastatic breast cl
Guidelines |
Patients with disease progression f
therapy should be offered an addi
HER2+targeted therapy since itis
HER2 pathway: The choice of the
previously administered therapy, r
preference änd access,

190. National
Comprehens
Can
Network

p
to docetaxel plus trastuzumab
ith placebo (median, 18.
P <.001)% At a median
cally significant
umab-containing regimen, with a
66; 95% Cl, 0.52-0.84) P=
tions reported in the
ol group were diarıhea (67% vs
Immation (27% ys: 20%), febrile
A 4%), Peripheral edema
rol group.“ Cardiac adverse
tion were reported slightly more
f was not citferentin the wo
fy, patients (n = 1436) with
nd no prior systemic therap
} taxel\paclitaxel, or
Juzumab until disease progression
results after 52 months of median
parable between docetaxel,
S reported was 19.6)23.0, and

the cytotoxic activity of the microt

maytansine),

In a phi II trial (MARIANNE), 41
metastatic breast cancer were ran)
T-DM1 with orwithout pertuzumaly
primary endpoints were safety anc
The PFS for T-DM1 with pertuzum
trastuzumab and a taxane (15.2 al
97.5% Cl, 0.69-1.08,,P = .14),5
non-inferiortó trastüzumab plus a
0:91; 97.5% Cl, 0.7: