Management of Early breast cancer

Management of Early breast cancer
Dr Veena P S
25/9/2021

Introduction
 Early breast cancer
Stage I and II
 Locally advanced
IIIA to IIIC

Work up
 History and physical examination
 Bilateral MMG/USG
 Core Biopsy-ER/PR/Her 2 neu, ,ki 67
 CBC/LFT/RFT
 No routine systemic imaging unless signs/symptoms present

Treatment
 Loco regional treatment Breast conservation therapy
  MRM +/- adjuvant Radiotherapy
 Systemic treatment  chemotherapy/Hormonal therapy
Based on tumor characteristics

BCT
Contra indications of BCS
• Pregnancy
•Diffuse suspicious micro
calcifications on MMG
•Widespread diseases that cant
be incorporated in lumpectomy
Relative contraindications
•Previous RT to chest wall/
breast
•Connective tissue disorders
•>5 cm tumors
•Includes lumpectomy + WBRT
•Indicated in early breast cancer
and DCIS
•Goal  optimal locoregional
control +better cosmesis
•No ink on margins is considered
as negative margins

Mastectomy
Indications
 Multicentric tumors
 Large size tumors compared to breast size
 Inability to achieve negative margins after multiple resections
 Prior RT to chest wall or other CI to RT
 Patient choice

Types of mastectomy
 Total mastectomy Removal of entire breast alone. No axillary
nodes/ muscles removed.
 Radical mastectomy  Entire breast + level I, II, III nodes+ Chest
wall muscles
 Modified radical mastectomy  Entire breast+ removal of level I
and II nodes. No muscles are removed.
 Partial Mastectomy  Removal of tumor with margins
 Skin sparing mastectomy
 Nipple sparing mastectomy

Radical/ total mastectomy / BCT
NSABP B 04 ( Fischer et al, N Eng J Med ;August 2002)
N=1079
Operable breast cancer
cN0 Radical mastectomy/Total mastectomy + loco regional
or axillary RT /Total mastectomy
cN1 RM / TM + RT
LRR
cN0  9% vs 5% vs 13%
(p=.002)
cN1  16% vs 14% (p=.67)
No significant impact in OS
NSABP B 06 ( Fischer et al, N Eng J Med ;October 2002)
N= 1851
EBC < 4cm
Total mastectomy/lumpectomy alone/ lumpectomy + breast
irradiation
IBTR after 20 yrs 39% vs
14% (p<0.001)
No difference in OS/distant
DFS in 3 arms
L L+RT
IBTR 39% 14%
(p<0.0001)
LRR RM TM+
RT
TM
cN0 9% 5% 13%
(p=.002)
cN1 16% 14%
(p=.67)
-

Surgical management of axilla
 Appx 20 to 40% of cN0 patients will be having pathologic evidence
of lymph node mets
 20% of stage I and II cN0 patients will develop axillary recurrence if
axilla is not addressed.
 Axillary node dissection is the std of care in clinically + node.
 Level I and II dissection is limited to patients with biopsy proven
axillary mets
 Minimum 10 nodes should be dissected
 ALND of level III is done only if gross disease is present in level II

SLNB
 SLNB is done by periareolar injection of a blue dye and checking the
node which turns positive
 It is indicated in clinically node negative tumors.
 No need of axillary dissection in SLNB negative tumors.
 When no SLNB is identified, level I and II, ALND is carried out.

ALND vs SLNB
RCT (Veronesi et al, N Eng J Med ; 2003)
cT1N0
SLNB
 ALND
SNLBALND if mets +
N=516
Accuracy of node detection is similar in
both groups.
No OS difference
ALMANAC trial (Robert Mansel et al ;JCNI ,2006 )
To asses the QOL of patients
cN0
N=1031
SLNB vs ALND
SLNB is associated with reduced arm
morbidity and better QOL

SLNB vs ALND
ACOSOG Z 0011 (Giuliano et al ; JAMA, 2017 )
cT 1-2 N0 with <3 sentinel nodes 
ALND vs SLNB alone
N=446
9.3yr median F/u
IBCSG 2301 (Galimberti et al; Lancet, April 2014 )
cT1/2 N1 SLNB with one more micro
metastatic node<2mm
ALND vs no ALND
N=931
Median f/u= 5 yrs
ALND SLNB
OS 83.6% 86.3%(p=.85)
DFS 78.2% 80.2%(p=.85)
ALND No ALND
DFS 84.4% 87.8% ( p=0.0042)
OS 97.6% 97.5% (p=.73)

Radiation therapy
Indications in EBC
Breast RT
 WBRT +tumor bed boost as part of BCT
 APBI in selected cases after lumpectomy
Regional nodal irradiation
 All node positive cases
Chest wall irradiation after MRM
 All Node positive disease
 >5cm tumors

WBRT
 Several RCTs and meta analysis has shown improved local control
which translates to survival advantage with the addition of WBRT after
BCS (NSABP B 06, N Engl J Med 2002, EBCTCG metanalysis, Lancet November 2011)
 Conventional fractionation- 50 Gy in 25# with tumor bed boost of 10-
16GY in 5-10 fractions
 Current standard dose is 40 to 42Gy in 15-16# to breast. Boost of 10 -
16 Gy in 5 -8 fractions are given for tumor bed after lumpectomy

Adjuvant RT after lumpectomy
Vinh-Hung et al - Meta-analysis of survival in randomized trials comparing breast-
conserving surgery with or without radiation

This meta-analysis
demonstrated a
threefold reduction in
local relapse and a
small but significant
increase in survival with
the use of radiation
therapy following
lumpectomy
J Natl Cancer Inst 2004;96:115
Vinh-Hung et al - Meta-analysis of local
control in randomized trials comparing
breast-conserving surgery with or without
radiation

N=10801
17 RCT
RT VS no RT after BCS
BCS BCS+RT
First
recurrence
35% 19.3%
(p<0.00001)
15yr breast
cancer death
25.2% 21.4
(p=0.00005)
pN0, 15 yr
breast cancer
death
31% 15% (p<0.00001)
pN+ ,10yr
breast cancer
death
51.3% 42.8% (p=0.01)
one breast cancer death was avoided
by year 15 for every four recurrences
avoided by year 10 After breast-conserving surgery, radiotherapy
to the conserved breast halves the rate at which
the disease recurs and reduces the breast
cancer death rate by about a sixth.

Hypo vs conventional fractionation
Trial Regimen N Median
f/u
Local relapse
OCOG Canada (Whelen et al; N Eng J med,
2010 Feb)
T1/T2 N0M0 ,post BCS
50Gy/25# (612)
42.5Gy/16# (622)
10 yr 6.7%
6.2% 95% CI 2.5 to 3.5)
RMH GOC trial (Owen et al, Lancet 2006)
T1-III N0-N1,post BCS
50Gy/25# (470)
42.9Gy/13# (466)
39Gy/13# (474)
10yr 12.1%
9.6%
14.8% ( p=0.027)
START A (Haviland et al,Lancet 2013)
50Gy/25# (749)
41.6Gy/13# (750)
39Gy/13# (739)
10yr 7.4%
6.3% (p=.65) HR 0.91
8.8% p=.41 HR 1.18
START B (Haviland et al,Lancet 2013)
50Gy/25# (1105)
40Gy/15# (1110)
10yr 5.5%
4.3% (p=.21, HR=.77)

Hypo vs conventional fractionation
Regimen Results
UK FAST trial (Brunt et al, J clin
Oncol,May 2020)
T1/T2N0
Post BCS
N=915
50Gy/25#
30Gy/5# once weekly
28.5Gy/5#
No significant difference in
normal tissue effects in 3 arms.
Not powered enough to compare
the LR/tumor control
UK FAST FORWARD
TRIAL
(Brunt et al;Lancet,April 2020)
T1-3N0-1M0,post BCS
N=4096
5yr results
40Gy/15#
27Gy/5#
26Gy/5#
Incidence of loco regional
relapse/distant relapse and OS
were similar
40Gy 27Gy 26Gy
IBTR 2.1% 1.7% 1.4%

Role of post lumpectomy RT in elderly
Fyles et al; N Eng J Med,2004 sep
>/= 50 yr
T1/T2 N0, ER + tumor
Tam vs Tam +RT
N=769
Hughes et al ; N Eng J Med,2004
sep
>/= 70 yrs
T1N0M0,ER+
Tam vs Tam +RT
N= 636
PRIME II Kunkler et al;
Lancet 2015
>/=65 yrs
T1/T2 upto 3 cm N0 ,ER+
Adj Endo vs Endo +RT
N=1326
10yr results
At 5yr No RT RT
Local relapse 7.7% 0.6% (p<0.001)
DFS 84% 91%(p=0.004)
axillary relapse 2.5% 0.5%(p=0.0.49)
LR recurrence 4% 1% (p<0.001)
No difference between OS and DM in both groups
IBTR 9.8% 0.9%(p<0.00001)
No difference in DM and OS

Role of post lumpectomy RT in elderly
 Meta analysis by Matuschek et al (Radiation ocology,March 2017), 5 RCT and 3766
patients mostly elderly patients with early stage breast cancer treated
either with adjuvant endocrine therapy or with endocrine therapy+
WBRT after BCS
 The benefit of RT for elderly women is significant in terms of local
control, but this absolute benefit is relatively small and must be weighed
against comorbidities and other competing risks.
 For women with favorable T1/N0 receptor positive breast cancers,
tamoxifen alone is a reasonable option that should be discussed.

Tumor bed boost vs no boost
 Aim – to increase local control & decrease incidence of IBTR
 Rationale - Microscopic extension is unlikely beyond 1-2 cms from
tumor mass (Veronesi etal, Annals of oncology 2001)
 )
 Majority of failures are located at surgical resection site (75-80%)

EORTC 22881-10882 (Poortmans et al,cancer radiother, 2015)
N=5318
post lumpectomy  WBRT (50 Gy/25# )
No boost vs 16 Gy boost
(photon/electron/LDR)
ST. GEORGE AND WOLLONGONG
RANDOMIZED BREAST BOOST TRIAL (Eric
Hau et al ;IJROBP ,Nov 2010)
T1/T2 N0-1M0
Post lumpectomy WBRT 50Gy/25# vs
WBRT (45Gy/25 with boost 16Gy/8# with
elctron)
N=688
No difference in local control in both arms.
No
Boost
Boost
10 yr Local
recurrence
10.2% 6.2% (p <
0.0001)
20 yr IBTR 16.4% 12%
20 yr OS 61.1% 59.7% (p=0.323)
Fibrosis at
20 yr
1.8% 5.2 (p=0.00001)

LYON trial (Romestaing et al,IJROBP ,Nov 2001)
T1/T2 tumors, post lumpectomy 
WBRT 50 GY/20#
10Gy/4# electron boost vs No Boost
N=1024
Budapest boost trial (Polgar et al;Strahlenther onkol,
Nov 2002)
Stage I/II ,Post lumpectomy WBRT
(50Gy/25#)
No boost vs 16 Gy/8# with electrons or
12–14.25 Gy HDR
N=207
.
5yr No boost Boost
Local
relapse
4.5% 3.6%(p=0.044)
5.3yr Boost No Boost
Local tumor
control
92.7% 84.9% (p=0.049)
RFS 76.6% 66.2% (p=0.044)
CSS 90.4% 82.1% (p=0.053)

For patients younger than 50 years
old and in patients with high grade
invasive ductal carcinoma, the
boost dose reduced the local
relapse from 19.4% to 11.4% (P =
.0046; HR, 0.51) and from 18.9%
to 8.6% (P = .01; HR, 0.42),
respectively.

 NCCN advocates boost of 10 to 16 Gy in 4 to 8 # to high risk
individuals
 Can be delivered via enface electrons or photons or brachytherapy
 Boost volume includes the surgical bed plus an arbitrary margin of 1
to 2 cm
 For women with large breasts & deep seated tumors (>4cm below
skin) , interstitial brachytherapy boost can be considered- 10 to 20
Gy HDR/LDR
 Electrons – appropriate energy selected to allow 85 -90% isodose
line to encompass target volume & decrease dose to the lung
Energy – 9-16 MeV

Post mastectomy RT
 The rationale for post-mastectomy radiation is the prevention
of a local-regional recurrence.
 Clinically occult persistent disease in the operative site or
regional nodes could act as a source of distant metastases, and
eradication of this disease could result in an improvement in
disease-free and overall survival.

Post mastectomy RT in node+
Trial Inclusion Arms LRRS OS
British
columbia trial
N=318
f/u=20yr
Premenopausal
Post MRM
N+
Sx+chemo
No RT
RT
74%
90% (P=0.002)
34%
47% (p=0.03)
Danish 82b
N=1708
f/u= 10yr
Premenopausal
high risk
Stage 2/3
Sx+chemo
No RT
RT
68%
91% (p<0.001)
45%
54% (p<0.001)
Danish 82 c
N=1460
f/u=10yr
Postmenopausal
Stage 2/3
N+
Sx+/-
chemo+tam
No RT
RT
70%
92% (p<0.001)
36%
45% (p=0.01)

EBCTCG post mastectomy RT
First
recurrence
Breast cancer
mortality
ADpN0 1.5% 2%
Node positive 18% 8%
AD  1-3node+ 16% 8%
Ad>4node+ 19% 10%

EBCTCG post mastectomy RT
 The addition of radiation resulted in a statistically significant
decrease in isolated local-regional recurrence in all patients and a
significant improvement in overall survival.
 After mastectomy and axillary dissection, radiotherapy reduced both
recurrence and breast cancer mortality in the women with one to
three positive lymph nodes in these trials even when systemic therapy
was given
 Patients at highest risk for local-regional recurrence in these trials
were those with four or more positive axillary nodes & T3 tumours.

Post mastectomy RT in N0
4 RCT and 22 non RCT
Women of any age or menopausal status with
T1–4N0M0 breast cancer treated with
mastectomy without simultaneous reconstruction
and either axillary clearance or sentinel node
biopsy.
•If no risk factors risk of LRR 5%
• two or more risk factors15%
• In the meta-analysis of three
randomised trials of mastectomy
and axillary clearance (667
patients), the addition of
radiotherapy resulted in an 83%
reduction in the risk of LRR (P <
0.00001) and in a 14% improvement
in survival (P = 0.16)
•LRR is increased in the
presence
•LVSI
•Grade 3 tumour
• > 2 cm
• close margin
• pre-menopausal
•</=50.

 The role of RT in management of the regional lymphatics is
influenced by the risk of subclinical microscopic disease in
regional nodal basins and patterns of failure.
 This risk is in part determined by disease characteristics and
the extent of surgical evaluation of the axilla.

ALND RT
AMAROS trial
Positive SLNB
ALND vs Axillary
RT
N=4806
Median f/u= 6.1yr
Axillary
recurrence=0.54%
Lymphedema
40% at 1 yr
28% at 5yr
1.03% (p=NS)
22% at 1 yr
14% at 5yr (p<0.0001)
No difference in
PS or DFS
ALND vs axillary RT

No RNI RNI
MA.20 intergroup study
1832
Lumpectomy ALND and
adjuvant treatment WBRT
10 yr DFS
77%
82%
HR .76,
p-.01
Axillary + SCF + ips
IMN in upper 3 ICS
No OS diff
EORTC 22922/10925
N=4004
Central/median tumors post
surgery and adjuvant
11yr DFS
69.1%
BCM- 14.4%
72.1%
12.5%
HR=.82,p=.02
All regional nodes
including IMN
RNI vs No RNI

Role of IMN irradiation
DBCG IMN (Thorsen et al ,JCO, Nov 2015)
Effect f IMN in early node +BC
3089 patients
Right side disease IMN RT
Left side disease  No IMN RT
Median f/u =8.9yr
French RCT (Hennequein ;IJROBP,Aug 2013)
cN+/ central/medial tumors
N=1334
11.3yrs median f/u
No benefit of IMN irradiation on the overall
survival could be demonstrated: the 10-year
overall survival was 59.3% in the IMN-
nonirradiated group versus 62.6% in the IMN-
irradiated group (P=.8).
IMN RT No IMN RT
OS 75.9% 72.2% (p=0.005)
Breast cancer
mortality
20.9% 23.4% (p=0.03)
Distant recurrence 27.4% 29.7%

EBCTCG -RNI
8 trials 1961-78
Median f/u 9.2
estimated >8 Gy mean heart dose and likely nodal dose <85% in the nodal RT
arm.
2178 women
Nodal RT had no effect on breast cancer recurrence [ (RR)=0.98, 95% CI 0.85–
1.13, p=0.83] or breast cancer mortality (RR=1.05, 0.91–1.21, p=0.54), but
increased non–breast cancer mortality (RR=1.44, 1.20–1.73, p<0.0001), leading to
a net increase in any death (RR=1.18, 1.06–1.32, p=0.004).

EBCTCG -RNI
6 trials 1989–2003,
9.1yr median f/u
Nodal dose ≥85%, and estimated mean heart
dose <8 Gy
10,954 women,
nodal RT reduced breast cancer recurrence
(RR=0.86, 95% CI 0.79–0.94, p=0.0006),
breast cancer mortality (RR=0.81, 0.74–0.90,
p<0.0001) and overall mortality (RR=0.86,
0.80–0.93, p=0.0002).
No excess of non–breast cancer mortality
was apparent (RR=0.96, 0.79–1.18, p=0.71).
Recurrence rate ratios did not vary
significantly according to nodal
region(s) irradiated
(axilla/SCF/IMC), or the use of
adjuvant chemotherapy

RNI
SCF RT indications
•>4 +LN after axillary
dissection
•1-3 +LN with high risk
features
•Tumor size >5cm
•Node + sentinel lymph node
with no dissection unless risk
of axillary disease is very
small
•High risk with no dissection
Axillla RT
If adequate axillary clearance(>10 lymph
nodes)
– Decision to give axillary nodal RT
depends on no. of node involvement &
prognostic factors (gross extracapsular
tumor extension).
Axillary recurrences after complete AC – 1-2%

RNI
IMN RT
Unresolved issue. No consensus on value of IMN irradiation
central and medial lesions with positive axillary nodes
: +SLN in the IM chain
: +SLN in axilla with drainage to IMN on lymphosintigraphy
Clinical recurrence in IMN rare (<3%) even when RT not given
Pts with pathologically +ve axilla – IMN mets <5%
RT leads to fibrosis & cardiac problems

RT technique
 Can be delivered via 2D ,3DCRT/IMRT technique
 3DCRT– better conformation of dose to target tissues, increased
sparing of normal tissues , limiting dose to lungs & heart
 IMRT - further improve the dose distribution, but may also increase
the volume of tissue exposed to lower doses of radiation may
increase the risk of second malignancies
 Studies have shown – 50% reduction in cardiac mortality rate ( Muren et
al)

Simulation
 Supine position
 Breast board
 Immobilization devices (e.g plastic molds ) reproduce daily
positioning and minimize day-to-day set up errors
 Lateral decubitus position - large, pendulous breasts.
 Prone breast borad
Reduction of dose in the high-dose region to the irradiated
breast
Reduction of volume and dose to the underlying lung and heart
Reduction of scattered dose to the contralateral breast.

Fields
 Medial & lateral tangential fields – cover chest wall or
breast & lower axilla
 Single ant field – covers supraclavicular & upper axilla

Field borders
Tangential fields to chest wall or breast
 Upper border – 2nd ICS (angle of Louis) when s.c f used
When s.c f not – head of clavicle
 Medial border – at or 1cm over midline
 Lateral border – 2-3cm beyond palpable breast tissue – mid axillary
line
 Lower border – 2cm below opposite infra -mammary fold

Field borders
Anterior field for SCF
 Should cover lower 2/3rd of neck
 Upper border – thyrocricoid groove
 Medial border – at or 1cm across midline
 Lateral border – insertion of deltoid ms or medial 1/3rd of humerus
 Lower border – matched with upper border of tangential fields

RT planning
 The anterior chest wall slopes downward from the mid-chest to the
neck.
 To make the posterior edge of the tangential beam follow this
downward-sloping contour
- the collimator of the tangential beam may be rotated
- patient placed on a slant so that the slope of the chest wall is parallel
to the table.
- by means of a rotating beam splitter mounted on a tray without
rotation of the collimator
-using multileaf collimation.

Field matching
 Usually Mono-isocentric matching technique.
 Single isocenter is set at the match between the SCF and
tangential fields.
 The inferior portion of the beam is blocked for the SCF
treatment and the superior portion is blocked for the tangential
field, with no movement of the isocenter, resulting in an ideal
match using the asymmetric collimators
 Lungs and heart are shielded with MLC.

Central lung distance
 Impact of radiation technique on lung volumetric dose – largely
dependent on CLD in tangential set-up
 Perpendicular distance from post. tangential field edge to post part of
ant chest wall at centre of field
 Best predictor of % of ipsilateral lung vol. treated by tangential fields
 Dose to lungs must be limited & minimum possible lung tissue must
be irradiated

Central lung distance
 Usually 2-3cm of underlying lung included in tangential portals
 CLD >3cm , particularly in lt. breast - irradiation of significant vol.
of heart & lung
CLD (cm) %age of lung
included
1.5 6
2.5 16
3.5 26

Maximum heart distance
 The maximal heart distance (MHD) is the width of heart in the
tangent fields at its maximal level
 Maximal heart length (MHL)
is the maximal length in
tangential fields referring
to the heart contour in a
digitally reconstructed
radiograph (DRR

3DCRT planning
Steps in 3DCRT planning
 Simulation
 Transfer of images to TPS
 Contouring
 Beam arrangement and shaping
 Dose calculation
 Optimisation
 Plan approval and delivery
 QA

Radiation beam
Photons
 4-6MV linac /Co60
 If tangential separation wide (>22cm) – significant dose
inhomogeneity – can be minimized by using high energy photons
 Part of RT (50%) delivered using high energy (10-18MV) – to
maintain inhomogeneity throughout entire breast to 5% or less
 High energy photons helpful in larger breasts – decrease integral
dose
 But photon energies >6MV – under dose superficial tissues beneath
skin

Radiation beam
 Electrons – deliver minimal dose to underlying critical structures &
normal tissues – decreases lung dose
 Disadvantage – skin reactions (thinning of skin telengiectasia)
compromises cosmesis
 Chestwall  9-12 Mev

Dose constraints
structure RTOG 1005 criteria
Breast CTV D95% >/= 38Gy
D50% </= 43.2Gy
Boost CTV D95% >/= 9.5GyGy
V11Gy </=5%
Heart V16Gy </= 5%
V8Gy</=30%
Mean</=3.2Gy
Lung V16Gy</=15%
V8Gy</=35%
V4Gy</=50%
C/l lung V4Gy</=10%
C/l breast Dmax</=240cGy
D5%</=14cGy

APBI
 Accelerated partial breast irradiation to only tumor bearing quadrant
– shortens treatment time and healthcare costs.
 Logistical problems associated with integrating local and systemic
therapies would be eliminated.
 BCT becomes acceptable for more women.
 Additionally, toxicity to adjacent normal structures (i.e., heart,
underlying chest wall, contra lateral breast) could be reduced
significantly by decreasing the volume of irradiated tissue

Systemic treatment
 Chemotherapy
 Endocrine therapy
 Her2 targeted therapy

Adjuvant systemic treatment
 Prognostic factors  age, tumor size, grade, no of nodes involved,
ER/PR and Her2 status
 Adjuvant chemo is given if >10% increase in mortality from breast
cancer at 10 yrs

In ER/PR positive Her2 neu neg
 T1a  No adjuvant chemotherapy. Only endocrine alone
 >Ta1N0  multigene assay 
 If no multigene assay available depends on clinical characteristics
shared decision making

Oncotype Dx
 NSABP B 14 RT PCR study 21 gene assay
 <18 low risk
 18-31 intermediate
 >31  high
 If recurrence score >31  chemothera
Recurrence
score
% of
patients
Rate of distant
recurrence at 10
yr in %
Low risk <18 51 6.8
Intermediate
>/=18-<31
22 14.3
High >31 27 30.5%

TAILORx
Prospective validation of Oncotype Dx
 Used different scoring system

RxPONDER trial
 5,015 patients
 stage II/III breast cancer
1-3 node+ and a RS ≤ 25.
 Randomly assigned to receive chemotherapy followed by endocrine therapy
or endocrine therapy alone
 Median f/u=5.1 yr interim results
 Postmenopausal women with HR-positive, HER2-negative breast cancer with
one to three positive nodes and a 21-gene recurrence score (RS) of ≤ 25
(Oncotype DX) derived no further benefit from chemotherapy added to
endocrine therapy and can safely avoid adjuvant treatment

RxPONDER trial
 5.2% absolute improvement in the iDFS (89.0% vs. 94.2%, HR 0.54, 95% CI
[0.38, 0.76]; p = 0.0004) favoring chemotherapy followed by endocrine therapy in
premenopausal patients (1,665 patients).
 This benefit was greater in premenopausal patients with RS 14-25 than
in patients with RS 0-13, with a 5-year iDFS absolute benefit of 6.2%
and 3.9%, respectively.
 The number of positive lymph nodes did not predict iDFS
 A 1.3% absolute benefit in overall survival was noted in the
premenopausal group.

Adjuvant chemotherapy
EBCTCG meta analysis 1988
 14% absolute benefit with addition of chemotherapy in annual odds
of death
 > in premenopausal women
 Poly chemotherapy is better than mono chemotherapy
 Addition of CMF 23% absolute reduction in odds of death
 6months CMF = 12 months CMF

EBCTCG meta analysis 1995
 7% improvement in survival with the addition of antracycline
 6 CMF= 4AC
 Increasing doses of anthracycline improved benefit
 Triple drug antracyclines are superior to CMF in OS
 Magnitude of benefit is similar in all subgroups

Taxanes
 1.4 to 3% absolute gain in survival with the addition of taxane with
antracycline
 Sequential regimens are better than concurrent regimens
 Weekly paclitaxel is better than 3 weekly paclitaxel in DFS
 3 weekly Docetaxel is equivalent to weekly paclitaxel
 In a subgroup analysis ,weekly paclitaxel is better in TNBC
 4 TC> 4AC= 6 CMF
 TC can be considered in case of CI to antracycline
 low risk ER +,node neg cases

Dose dense chemotherapy
Principle
 Skipper–Schabel–Wilcox model, cell kill follows first order kinetics:
tumor growth is exponential and cytotoxic chemotherapy removes a
constant fraction of cells
 Norton–Simon hypothesis dictates that the rate of cancer cell death
as a result of cytotoxic treatment is directly proportional to the tumor
growth rate at the time of its administration
 2% improvement in breast cancer mortality in EBCTCG meta
analysis
 5 to 6% improvement in PFS and 3 to 6% improvement in OS

ASCO- adjuvant chemo in HR+
 In patients who can tolerate it, use of a regimen containing anthracycline-taxane
is considered the optimal strategy for adjuvant chemotherapy, particularly for
patients deemed to be at high risk.
 For patients with high-risk disease who will not receive a taxane, an optimal-dose
anthracycline three-drug regimen (cumulative dose of doxorubicin > 240 mg/m2
or epirubicin > 600 mg/m2 but no higher than 720 mg/m2 ) that contains
cyclophosphamide is recommended. The cumulative dose of doxorubicin in two-
drug regimens should not exceed 240 mg/m2 .
 For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-
methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable
chemotherapy alternative to doxorubicin-cyclophosphamide

Role of adjuvant endocrine therapy

 A tumor is said to be endocrine responsive ,if >10% of cells are
positive by IHC
 Available modalities are
Temporary Permanent
SERM AI SERD LHRH
agonist
Tamoxifen Letrozole Fulvestant Leupride
Anastrazole
Exemestane
Surgical
ablation
XRAM

Several trials have shown that adjuvant tamoxifen will add to DFS and 2 trials
have shown OS benefit also
1988 EBCTCG meta analysis
 ER expression predicts the responsiveness of therapy
 Tamoxifen increases the RFS and OS
 Both N0 and N+ patients have benefit in RFS and OS
 More benefit in N0 patients
 Optimal duration is 5 yrs
 11.5% absolute benefit in RFS and 9% absolute OS benefit
 16% absolute benefit in odds of death

EBCTCG meta analysis 2015 AI
 3.6% gain in RFS with AI over Tam at 10ys
 3.5% distant recurrence gain with AI over Tam at 10ys
 2.5% gain in OS with AI over Tam at 10yrs
 PR neg had higher gain
 Node + has higher gain
 2.8% more bone loss with AI at 10yrs
 0.2% gain in endometrial carcinoma with AI

 5yrs of AI reduces the 10yr breast caner mortality by atleast 40%
compared to no endocrine therapy
 AI is more effective than Tam in preventing breast cancer death
 Higher chance of recurrence is seen few years after diagnosis. Hence
better to start with AI than with Tam
 Once the patient is diseases free, switching to tam is similarly
effective to continuation of AI

 Which AI is better?
FATA GIM 3 study all the 3 – Anastrazole, Letrozole and
Exemestane are equal
 Timing
4 to 6 weeks after surgery
DFS is better if give sequentially with chemotherapy
Concurrent /sequential with RT

Extended duration of tam
 ATLAS(adjuvant tamoxifen shorter against longer)
 aTTOM (adjuvant tamoxifen treatment offer more)
Tam x
5
Tam x
5
Placebo
EBC
Any ER
/ER untested
(attom)
Any age/node

Pooled analysis
 Decreased risk of recurrence beyond 10 yr with extended treatment
 Continued reduction in risk of recurrence and breast cancer
mortality from 7 yr onwards
 10 yr Tam can decrease the breast cancer mortality by 1/3 in first
10yrs and ½ in 2nd decade

Extended AI after tam
Arms DFS OS
MA 17
Postmenopausal
Median f/u=30 mon
n=5187
Letrozole x 5yrs
Placebo
94.4%
89.8% (p=0.01)
96%
94% (p=0.83)
NSABP 33
Postmenopausal
Median f/u=30 mon
N=1588
Exemestane x 5yr
Placebo
91%
89% (p=0.07)
No OS benefit
RFS benefit +
ABCSG 6a trial
Post menopausal
Median f/u=5 yrs
N=856
Anastrazole x 3 yrs
Placebo
RR 7.1%
11.8% (p=0.031)
No OS benefit
RFS and DM
benefit+

Extended AI after AI
 MA 17R
 NSABP B32
 IDEAL
 SOLE
 SALSA
 AERAS

Extended AI after AI
Study Randomisation N Med
ian
f/u
DFS OS
MA 17R Lx 5
L x 5yr
Placebo
1918 6.3
95%
91% (p=0.01)
93%
94% (p=.83)
NSABP
B 42
Lx 2-3 yrs+/tam
L x 5yr
Placebo
3936 9.3
76
72.1 (p=0.011)
86
85.5 p=0.0003)
DR benefit
+

IDEAL
trial
5yr endocrine trt
Let x 2.5yr
5yr
1824 6 No difference in DFS/OS in either arm
SOLE
trial
4-6 yrs endo
Let x5yrs
continuously
Intermittent
9mon3mon
break/yr
4884 5 No diff in DM/OS/DFS in both the arms
SALSA 5 yr endo 
Anastrazole x 2
x 5
3484 8 No difference between DFS and OS,but
high risk of bone fracture in 5 yr group
AERAS Anas x 5 or tam 2-
32-3 yr anas
5 yr anas
observation
1697 4.9 5% improvement in DFS. No OS benefit.
Increased risk of fracture in 5yr group

Extended AI
12 randomised trials that
compared 3-5 years of AI
versus no further treatment
after five or more years of
endocrine therapy.
Extended AI therapy after approximately 5 years of
tamoxifen:
• 33% risk reduction for any recurrence
5-year gain of 3.6% (P < .00001)
• 23% reduction in the risk of distant recurrence
5-year gain of 1.5% (P = .008)
•23% reduction in breast cancer mortality
5-year gain of 0.8% (P = .05)

Extended AI
Extended AI therapy after 5 years of an
AI alone
• 24% risk reduction for any
recurrence, with a 5-year gain of 1.2%
(P = .02)
• 22% risk reduction in distant
recurrences, with a 5-year gain of
0.3% (P = .09)
• 1% risk reduction in breast cancer
mortality, with a 5-year loss of 0.2%
(P = .97)
Extended AI after 5 to 10 years of tamoxifen,
then an AI:
•16% risk reduction for any recurrence, with a
5-year gain of 2.1% (P = .002)
• 8% reduction in the risk of distant
recurrence, with a 5-year gain of 1.0% (P =
.29)
•7% reduction in breast cancer mortality, with
a 5-year gain of 0.2% (P = .45).

Extended AI
 The impact of extended AI on recurrence depends on the type of
prior endocrine therapy
 Among women treated with prior tamoxifen, the risk reduction was
larger, 33% (P < .00001), compared to women who received AI for at
least part of their initial endocrine therapy (19%; P = .00010).
 Risk reduction is apparent in the first 2 years after prior tamoxifen
but not until the third year after prior AI therapy.
 The absolute benefits increase as more nodes are involved.
 The occurrence of bone fractures also increased by 24% with
extended endocrine therapy.

ASCO recommendations for optimal AI-2019
 For node-negative patients, the use of extended AI therapy for up to 10
years should be based on an assessment of established prognostic
factors for recurrence risk.
 For women with node-positive BC, AI therapy should be continued for
up to 10 years.
 For women on extended AI therapy, 10 years should be the maximum
duration of therapy.
 For women using or contemplating extended AI adjuvant treatment,
this decision should be part of a shared process between the clinical
team and the patient, with all involved weighing the risks and benefits of
prolonged treatment.

ASCO recommendations for optimal
AI-2019
 When extended adjuvant hormonal therapy is indicated, any of the following regimens
may be utilized:
 AI for up to a total of 10 years
 tamoxifen for 2 to 3 years followed by AI for 7 to 8 years
 tamoxifen for 5 years followed by AI for 5 year
 tamoxifen for 10 years
 Relative benefits for extended adjuvant endocrine therapy were greater in women
who switched from tamoxifen to AIs.
Less benefit may be seen among women who continue tamoxifen for 10 years or who
are treated with AIs in the first 5 years and then continue on AI therapy.
 AI therapy is recommended during the course of adjuvant endocrine therapy, if a
patient is intolerant to AIs, does not want to take AIs, or is premenopausal, the use of
tamoxifen is recommended.

Ovarian suppression in premenopausal

8 yr updated results of combined analysis
E+OF
S vs
T+OF
S
With
chemo
Witho
ut
chemo
HR Comb
ined
DFS 3% 2% 0.74 4%
OS 2% 1% 0.86 2%
Freedo
m
from
DR
2.4% 2% 0.6 No
diff
T+OFS vs T Absolute
benefit
DFS 7%
OS 4.3%
•E+OFS results in sustained and
consistently higher DFS and freedom from
distant recurrence
•Relative treatments were similar whether
they received chemo or not
•Absolute benefit more in women who
remained pre menopausal after chemo
•In woman with high risk clinico
pathological factors
5.3 percent point DFS benefit with
T+OFS vs T alone
7 percent points higher DFS with
E+OFS

St Gallens-2021
Endocrine treatment chemotherapy
T1a AI/T x 5 yr No
T1b AI/T x 5 yr +/-
Individualised decision
making
T1c AI/T x 5 yr
Stage 2 node neg and
premenopausal
OFS+T/AI
Stage 2 node neg and post
menopausal
=/-extended AI
Stage 2 node+ Extended AI

Pre op systemic therapy
Rationale 
 Can render inoperable tumor to operable
 Downstaging  increased BCS rate
 Eliminate micro metastasis
 Better prognostic information based on the response to therapy
 Allow app time for genetic testing
 Can tailor the adjuvant treatment (TNBC)

Candidates of NACT
 Those with big tumors and want BCS
 Those subtype with high likelihood of response- her2 + and TNBC
>T1 or >/=N1
CI
 Extensive insitu disease
 Poorly defined extent/not palpable/clinically accessible

Preop vs post op chemo?
 NSABP B 18
TI,2,3,N0,1,M0
Operable breast
cancer
AC x
4Sx+/-RT
Sx+/- RT
AC x 4
No difference between adjuvant
and neoadjuvant treatment in DFS
or OS in patients with stage II or
stage III breast cancer who were
randomly assigned to AC either
before or after surgery

Neoadjuvant endocrine therapy in post
menopausal
Eligibility NACT arms Outcome
IMPACT
Study
Phase 3
ER+
Operable breast
cancer
Tam x 3mon
Anastrazolex
3mon
Tam+Anas x
3mon
•No SS differences among the three treatment
groups in tumor objective response
•A significantly higher proportion of patients
were deemed by their surgeon to be eligible for
BCS after treatment with anastrozole (46%)
versus with tamoxifen (22%, P 5 .03)
Semiglasov
et al
Phase 2
ER+
IIA to IIIB)
AT x 4
Anastrazole
x 3mon
Exemestane
x 3mon
•Clinical objective response was 64% in the
endocrine therapy and chemotherapy treatment
groups.
•Rates of pcr(3% vs 6%) and disease progression
(9% vs 9%) did not differ significantly in the
endocrine therapy or chemotherapy group,
respectively (P > .05).
•Rates of breast-conserving surgery were slightly
higher in the endocrine group (33% vs 24%; P

NACT in ER+
20 RCT
N=3490
18 of which
included only
post menopausal
•Neoadjuvant AI were more effective (better
clinical response rate and BCS rate) than
tamoxifen
•No differences observed in clinical
response rate between endocrine
monotherapy and dual endocrine therapy.
•Response rates and BCS rates with AI
based neoadjuvant endocrine monotherapy
were comparable with those observed with
combination neoadjuvant chemotherapy.
• Toxicity was significantly greater in the
neoadjuvant chemotherapy arms

Neoadjuvant endocrine therapy in HR+
premenopausal
STAGE trial
Phase 3
ER+
Operable
breast
cancer
N=204
Anastrazole +
Goserlin
monthly x
6mon
Tam+Goserlin
monthly x 6
mon
More patients in the anastrozole group had a complete or partial
response than did those in the tamoxifen group during 24 weeks
of neoadjuvant treatment (anastrozole 70·4% vs tamoxifen
50·5% .
Estimated diff erence between groups 19·9%, 95% CI 6·5–33·3; p=0·004).
No significant differences were observed in the quality-of-life
measures,
Kim et al
Phase 3
HR+,
Her 2neg
Node+
N=187
Ac x 4 Doce
x 4
Tam + Goserlin
mon thly x
6mon
More NCT patients had complete response or partial response
than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI
17.6–44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4–
24.9, p = 0.046).
Better clinical responses were observed in pre-menopausal
patients after 24 weeks of NCT compared to those observed after
NET.

ASCO –NACT in HR+
 Neoadjuvant chemotherapy can be used instead of adjuvant
chemotherapy in any patient with HR-positive, HER2-negative breast
cancer in whom the chemotherapy decision can be made without
surgical pathology data and/ or tumor-specific genomic testing
 For postmenopausal patients with HR-positive/HER2-negative
disease, neoadjuvant endocrine therapy with an AI may be offered to
increase locoregional treatment options. If there is no intent for
surgery, endocrine therapy may be used for disease control
 For premenopausal patients with HR-positive/HER2-negative early-
stage disease, neoadjuvant endocrine therapy should not be routinely
offered outside of a clinical trial

TNBC-Adjuvant
 In CALGB
9344
N+
EBC
 Sparano et al
N+
high risk Node neg EBC
AC x 4 weekly pacli/q3w Pacli/weekly doce/q3w doc
TNBC and her2 over expressers
had better survival
TNBC benefitted more with weekly
Pacli

TNBC-Adjuvant
 Dose dense chemo
CALGB9741
TNBC benefited more
with improved DFS and OS

NACT in TNBC
Role of Carboplatin
 GEPAR SIXTO trial
 CALGB 40603
 Brightness trial
 Role of Capecitabine
Create X trial
SYSUCC trial
ECOG ACRIN 1131 trial

Carboplatin in TNBC
 GEPAR SIXTO
Phase2
Stage 2/3
TNBC
Her2+
 CALBG 40603
Phase 2
Stage2/3
TNBC
Pacli+doxo+bevaci+/-
anti her2 +Carbo
Pacli+doxo+bevaci+/-
anti her2
20% absolute
improvement in
PCR in TNBC
with Carboplatin
((p=0·005))
No improvement in OS /DFS

Carboplatin in TNBC
Improvement in pcr with carboplatin,not with veliparib

Role of Capecitabine in TNBC
CREATE X trial
Her2 neg
Residual tumor after
NACT
Capecitabine
(1.25gm/m2 D1-D14
BD q3w x 6-8 )
Observation
OS (4%,p=0.01)and DFS(6%, p=0.01)
benefit present with the addition of
capecitabine.
Better results in TNBC arm
SYSUCC 001 trial
EBC
TNBC after
NACTSX+/-RT
Capecitabine
(625mg/m2 contiously
x 1yr
Observation
5-year DFS was 82.8% in the capecitabine
group and 73.0% in the observation group
([HR= 0.64 [95% CI, 0.42-0.95]; P = .03)
5-year OS was 85.5% vs 81.3% (HR, 0.75 [95%
CI, 0.47-1.19]; P = .22),
ECOG ACRIN 1131
Stage2/3 TNBC
>1cm residue post
NACT and Sx
Carboplatin
Capecitabine
Ongoing trial
Interim results
Platinum agents do not improve outcomes in
patients with basal subtype TNBC RD post-
NAC and are associated with more severe
toxicity when compared with capecitabine

TNBC
 T1a chemo case by case
 T1b TC / ACT
 Stage 2  NACT is preferred AC T +/- Platinum
 Residual tumor after NACT add capectabine

Asco update on NACT
 Patients with TNBC who have clinically node-positive and/or at least
T1c disease should be offered an anthracycline- and taxane-
containing regimen in the neoadjuvant setting
 Patients with cT1a or cT1bN0 TNBC should not routinely be offered
neoadjuvant therapy outside of a clinical trial
 Carboplatin may be offered as part of a neoadjuvant regimen in
patients with TNBC to increase likelihood of pCR
 There is insufficient evidence to recommend routinely adding the
immune checkpoint inhibitors to neoadjuvant chemotherapy in
patients with early-stage TNBC

Her 2 + EBC
 Role of Traztuzumab
 Pertuzumab
 TDM1
 Neratinib

Role of TZB
 EBCTCG meta analysis on Tzb in EBC-2021
 7 RCT ; 13864 women
 Median f/u=10.7yr
 the addition of trastuzumab to chemotherapy reduces recurrence of,
and mortality from, breast cancer during the first decade of follow-
up by about a third
 10-year absolute reduction of 9·0% in recurrence and of 6·4% in
breast cancer mortality, compared with chemotherapy alone
 Concurrent TZB is better than sequential (5% improvement) 30 -40%
improvement in DFS and OS with the addition of traztuzumab
 10 -13% absolute improvement in survival by 1 year of TZB

Role of TZB
APT trial Phase 2
410 =n
Median f/u
= 6.5yr
N0
</=3cm
Her2 +
Pacli(80
mg/m2) with
tzb x 12 wk
 tzb for 9
mon
DFS -93% (95% CI, 90.4 to 96.2)
OS- 95% (95% CI, 92.4 to 97.7)
RFI -97.5%
PERSEPHONE
Trial
Phase 3
N=2054
Median
f/u=5.4yr
Her2 +
EBC
Eligible for
chemo
TZB x 6mon
TZB x 1 yr
DFS 89·4% (95% CI 87·9–90·7) in the
6-month group and 89·8% (88·3–
91·1) in the 12-month group
(HR1·07 [90% CI 0·93–1·24], non-inferiority
p=0·011)
6-month TZB is non-inferior to
12-month with less cardiotoxicity
and fewer severe adverse events
6 month vs 1yr TZB
Very low risk group

Role of pertuzumab
IDFS analysis based on 508 events (intent-to-treat population) showed a hazard
ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for
pertuzumab and placebo groups, respectively.
No OS benefit

Role of TDM -1
KATHERINE
trial
Phase 3
N=1486
Her2+
EBC wit
residual after
NACT
Adj TDM x 14
cycle
TZB x 14 cycle
Interim results
iDFS was significantly higher in the
T-DM1 group than in the Tzb group
(HR for invasive disease or death, 0.50; 95% CI, 0.39 to
0.64; P<0.001).
the risk of recurrence of invasive
breast cancer or death was 50%
lower with adjuvant T-DM1 than
with trastuzumab alon
ATTEMPT trial
Phase 2
N=497
Stage 1
Her 2+
TDM -1 x 1yr
Pacli q w x
12wk+Yzb x 1 yr
Complete results not out yet
3-year iDFS for T-DM1 was 97.8%
(95% CI, 96.3 to 99.3)

Neratinib in EBC
 Role of neratinib
 Exe net study
 Role of TDM1
 Katherine trial
Absolute iDFS benefits at
5 years were 5.1% in
HR+/≤ 1-year (HR, 0.58; 95% CI
0.41-0.82) and 1.3% in
HR+/>1-year (HR 0.74; 95% CI,
0.29-1.84).
In HR+/≤ 1-year, neratinib
was associated with a
numerical improvement in
OS at 8 years (absolute
benefit, 2.1%; (HR, 0.79; 95%
CI, 0.55-1.13)

ASCO update on NACT
 Patients with node-positive or high-risk node-negative, HER2-
positive disease should be offered neoadjuvant therapy with an
anthracycline and taxane or non–anthracycline-based regimen in
combination with trastuzumab. Pertuzumab may be used with
trastuzumab in the neoadjuvant setting
 Patients with T1a N0 and T1b N0, HER2-positive disease should not
be routinely offered neoadjuvant chemotherapy or anti-HER2 agents
outside of a clinical trial

Bisphosphonates in EBC
EBCTCG 2015
 Fewer bone recurrence [ 2·2%absolute gain at 10yr (95% CI 0·6–3·8)]
/distant recurrence [(RR 0·82, 0·74–0·92; 2p=0·0003)]and breast cancer
mortality [3·3% absolute benefit at 10 yr (95% CI 0·8–5·7)] with
bisphosphonates.
 More benefit in postmenopausal ladies
 Benefit is similar with amidronate / zolendronate / ibandronate
 Low intensity osteoporotic schedules(6monthly) have similar benefit
when compared with high intensity regimens
 Average effect is similar with 2yr treatment and 3-5 yrs treatment
 1.3% reduction in fracture risk in year 2-4

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