004 Breast Cancer

Thursday, August 22, 2013
REVIEW "BREAST CANCER"

TREATMENT
2013
Aumkhae Sookprasert, MD
Medicine department, KKU
4avv:sutnasnvu:tv4nannvtatsuusnn
APOPS 6th
v:u:tvunv (1,2)
(Early stage breast
cancer)
v:u:anaau (3)
(Locally advanced
stage breast cancer)
v:u:unvnv:vau (4)
(Metastatic stage)
EARLY STAGE BREAST CANCER
(EBC)
IN THE PAST
Prognosis in early stage depend on staging

TODAY'S UNDERSTANDING
Prognosis in early stage depend on biology !

(nature or aggressiveness of cancer)
TISSUE MICROARRAYS IN BREAST
CANCER
PROGNOSIS VARY BY MOLECULAR
SUBTYPES
Luminal A has best prognosis
Basal & HER2 subtypes has worst
prognosis
HER 2
E
THE "MUST" HAVE IHC IN
EVERY BREAST CANCER
Ki-67
HER2 positive =
3+
ER positive = at least
1% staining
4 TYPES OF BREAST CANCER
CORRELATION BETWEEN MOLECULAR AND IHC
Intrinsic
Subtype
Clinics-
pathological
surrogate
denition
Notes
Luminal A
Luminal A like
All of the
following
ER + and PR +
HER2 -
Ki-67 low
Ki-67 <14 best
correlate
PR cut-point >/
= 20%
Luminal B
Luminal B like :
HER 2 negative
ER+,HER2- and
at least 1 of
- Ki-67 high
- PR low
ER +
HER2 +
Any Ki-67
Luminal B like :
HER 2 positive
ER+, HER2 +
And any PR or
Ki-67
Erb B2 over
expression
HER 2 +, non-
luminal
HER2 +
ER and PR
absent
Basal-like
Triple negative
ductal
ER and PR
absent
HER 2 negative
SYSTEMIC TREATMENT RECOMMENDATION
Subtype Type of therapy Notes
Luminal A-like
Luminal B-like
(HER2 negative)
Luminal B-like
(HER2 positive)
HER 2 positive
(non-luminal)
Triple negative
(ductal)
ET is the most
critical
intervention and is
often used alone
Cytotoxic may be added
- Gr 3
- Involvement of 4 or more
LNs
- Age < 35 (50%)
ET for all, CT for
most
Cytotoxics + Anti-
HER2 + ET
Cytotoxics + Anti-
HER2
Cytotoxics
Surgery
Chemotherapy
4 - 6 cycles every 3 weeks
Radiation
( size > 5 cms, lymph node involvement)
(ER and PR and HER2 negative)
Triple negative subtype
Surgery
Chemotherapy
Radiation
( size > 5 cms, lymph node
involvement)
(ER positive and HER2 negative)
Luminal subtype (A & B)
Anti-hormonal
5 yrs
+ / -
Esp Luminal subtype (B)
HER2 negative
Surgery
Chemotherapy
Radiation
involvement)
(ER negative and HER2 negative)
HER 2 positive, non-luminal
Anti- HER 2
(Trastuzumab )
1 yr
+
Surgery
Chemotherapy
Radiation
involvement)
Luminal B - HER2 pos
Anti- HER 2
(Trastuzumab )
1 yr
+
Anti-hormonal 5 yrs
Guidance of adjuvant CT in "TNBC" from St Gallen
2013
The panel was clearly the opinion factors arguing the use of
Chemotherapy include
- Grade 3 tumor
- High Ki-67
- Low level of HR status
- HER2 positive
- Triple negative status
- Involvement of > 3 LNs
Guidance of adjuvant CT from St Gallen 2013
For patients with "Luminal A"
Less responsive to CT
CT should be added in large tumor volume
1st & 2nd generation : CMF, AC, FAC, TC could be
considered
For patients with "basal-like" (triple negative ductal)
disease.
The panel strongly endorsed both anthracyclines and
Taxanes, and did not believe that platinum or regimens
emphasizing alkylating agents were specically required.
No clear consensus regarding dose-dense
For patients with "luminal B" (HER2 negative)
Majority : CT to be indicated
CT regimen should contain Anthracyclines (and slim
majority Taxanes)
50% agreed to have such chemotherapy for 6 cycles
Type and chemotherapy regimens
Non - Anthracyclines Anthracyclines - based A + T based regimens
Concurrent A then T sequential A then T
TAC x 6
AC x 4 then wP x 12
FEC(100) x3 then D(100 )
x3
ACx4 then Px4
TC x 4
(75 / 600) q 3
CAF
(Co,A30x2,F500x2)
FAC x 6
(600 / 50 / 600)
CMF x 6
(oralC,D1,8 M & F)
AC x 4
(60 / 600) q 3
High risk : TN, HER2 pos
Lower risk of recurrence
Surgery
Anti-hormonal
5 yrs
Pre-menopausal
- TAM 10 yrs (ATLAS trial)
Post-menopausal
Surgery
Anti-hormonal
5 yrs
Pre-menopausal
- TAM 10 yrs (ATLAS trial)
Post-menopausal
should include AIs
- AI x 2 then TAM x 3
- TAM x 2 then AI x 3
- TAM x 5 then AI x 5
Surgery
Chemotherapy
Anti- HER 2
(Trastuzumab )
1 yr
+
- should include A and T
- Concurrent Taxanes + Trastuzumab is the most efcacious
- Sequential CT then Trastuzumab : decrease cardiotoxic
- Concurrent TCH is reasonable for pts with lower risk of recurrence
Surgery
Chemotherapy
Anti- HER 2
(Trastuzumab )
1 yr
+
- Trastuzumab is the only anti-HER2 in adjuvant setting
- Standard duration is still 1 yr
Treatment duration
Does 1 yr optimal ?
Treatment
duration
6 months vs 1 year
PHARE
Persephone
9 weeks vs 1 year
SHORT-HER
SOLD
1 year vs 2 years
HERA
> 1.15 : non-inferiority not proved
ADVANCED BREAST CANCER
ABC
(survival) QoL
Factors
1. Patient's factor : Performance status
2. Tumor's factor : Biology (tumor subtype)
3. Treatment's goal
- Rapid response in patient with widespread metastasis
- Toxicity proles in each treatment
ER and PR and HER2 negative
ER and/or PR positive
and HER2 negative
HER 2 +, ER / PR -
Chemotherapy
Anti-hormonal Anti-HER 2
Triple negative tumor
ER positive tumor HER2 positive tumor
WHAT'S NEW IN CHEMOTHERAPY FOR
ABC
New kid in the block : Erlibulin

FAC
Taxanes
Capecitabine
Vinorelbine
Gemcitabine Ixabepilone
Chemotherapy
1
2
3
4,5,6
FAC
Taxanes
Capecitabine
Vinorelbine
Gemcitabine Ixabepilone
Chemotherapy
1
2
3
4,5,6
Eribulin
Study 301: PFS
PFS similar with eribulin compared with capecitabine
Survival Outcome
Eribulin
(n = 554)
Capecitabine
(n = 548)
HR
(95% CI)
P Value
Median PFS, mos

Independent review 4.1 4.2
1.079
(0.932-1.250) .305
Investigator review 4.2 4.1
0.977
(0.857-1.114) .736
Kaufman PA, et al. SABCS 2012. Abstract S6-6.
WHAT'S NEW FOR ANTI-HER2 FOR
ABC
New kid in the block : Pertuzumab and T-DM1

Trastuzumab Lapatinib
Anti-HER 2
1 2
Pertuzumab
+
First line Px Second line
T-DM1
3 or later line of
therapy
Trastuzumab block process of
homo-dimerization of HER 2 protein
(Ligand - independent)
!
Trastuzumab bind to
subdomain 4
!
Preferentially inhibits ligand-
independent HER2 signalling
!
Prevents shedding of HER2
ECD
!
Flags cells for destruction by
the
immune system
Baselga J. 2012
Block by
Trastuzumab
Pertuzumab and Trastuzumab Bind to Distinct Extracellular
HER2 Epitopes
Hubbard SR. Cancer Cell. 2005;7:287-288.
Pertuzumab-HER2
Complex
Trastuzumab-HER2 Complex
Pertuzumab
Trastuzumab
III
II
I
Inhibits HER2 dimerization with other
HER family receptors (particularly HER3)
Activates ADCC
Inhibits multiple HER-mediated signaling
pathways
Activates ADCC
Inhibits HER-mediated signaling
pathways
Prevents HER2 domain cleavage
III
II
I
IV
IV
"Twin Action for Trastuzumab plus Pertuzumab"
Primary end point : Independent assessed PFS
Swain S, et al. ASCO 2013
Significant improvement in PFS
compare to Trastuzumab +
Docetaxel
Secondary end point : OS
Significant improvement in
OS compare to
Trastuzumab + Docetaxel
3 yr OS increase by 16%
NNT = 6.25
Swain S, et al. ASCO 2013
Trastuzumab Lapatinib
Anti-HER 2
1 2
Pertuzumab
+
First line Px Second line
T-DM1
3 or later line of
therapy
Highly potent cytotoxic agent
Cytotoxic agent: emtansine (DM1)
Monoclonal antibody: trastuzumab
Target expression: HER2
Systemically stable
Linker: SMCC
T-DM1
Average
drug:antibody
ratio ! 3.5:1
Trastuzumab/Emtansine:
Novel AntibodyDrug Conjugate
Trastuzumab
MCC
DM1
T-DM1 selectively delivers a highly toxic payload to
HER2-positive tumour cells
T-DM1 binds to the HER2
protein on cancer cells
Receptor-T-DM1 complex is
internalised into HER2-
positive cancer cell
Potent antimicrotubule
agent is released once
inside the HER2-
positive
tumour cell
12.9% difference
Stratified HR: 0.682 , P = .0006
Next step of Anti-HER2 in ABC
WHAT'S NEW FOR ANTI-HORMONAL
IN ABC
New kid in the block : m-TOR inhibitor

Nucleus
Growth &
proliferation
Methods to inhibit ER
TAMOXIFEN
1. NS-AIs : LET, ANA
2. S-AI : EXE
OFS
(GnRH or
surgical)
Pre-menopausal
Post-menopausal
FULVESTRANT
Anti-hormonal
Tamoxifen
Fulvestrant
Non-steroidal AIs : Letrozole, Anastrozole
steroidal AI : Exemestane
Megestrol acetate
Estrogen
Chemotherapy
Anti-hormonal
Anti-HER 2
Pre-menopausal
TAM
OFS + ET as
post
menopausal
Anti-hormonal
Tamoxifen
Fulvestrant
Megestrol acetate
Estrogen
Anti-hormonal
Post-menopausal
NS-AIs
(Letrozole, Anastrozole)
S-AI
(Exemestane)
TAM
Fulvestrant
Anti-hormonal Reverse or delay resistance
mTOR inhibitor Tamoxifen
Fulvestrant
Megestrol acetate
Estrogen
Chemotherapy
Anti-hormonal
Anti-HER 2
Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369.
HR+ Advanced Breast Cancer
E
mTOR inhibitor
X
Anti-hormonal
Tamoxifen
Fulvestrant
Megestrol acetate
Estrogen
Anti-hormonal
Post-menopausal
NS-AIs
(Letrozole, Anastrozole)
S-AI
(Exemestane)
TAM
Fulvestrant
+ Everolimus
Primary end point : Independent assessed DFS
Timeline of Approval for HR+ Advanced Breast Cancer:
No New Regimens Approved in the Prior Decade
Tamoxifen
(1977)
Letrozole
(1997)
Fulvestrant
(2002)
Everolimus +
exemestane
(2012)
1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
Exemestane
(1999)
Anastrozole
(1995)
Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

004 Breast Cancer

Uploaded by

Copyright:

Available Formats

You might also like

004 Breast Cancer

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

004 Breast Cancer

Uploaded by

Copyright:

Available Formats

Thursday, August 22, 2013

REVIEW "BREAST CANCER"

Prognosis in early stage depend on staging

Prognosis in early stage depend on biology !

New kid in the block : Erlibulin

New kid in the block : Pertuzumab and T-DM1

New kid in the block : m-TOR inhibitor

You might also like