Her2Neu positive breast cancer is comprises of about 15-20% of all breast cancer. Among them quite a few number of patients present as de novo metastasis . In this presentation you ll find a guide how to manage it with relevant evidences. Presentation is meant for Oncology trainees.

1. MANAGEMENT OF
METASTATIC HER2 POSITIVE
BREAST CANCER
DR KOUSTAV MAZUMDER
CONSULTANT ONCOLOGIST
CHITTARANJAN NATIONAL CANCER INSTITUTE, KOLKATA

2. INTRODUCTION
• Accounts for 15-20% of breast cancer cases
• incidence of Her2 positivity in Indian population is between
26% and 50%
• Treatment is palliative
• Survival affect on ER / PR status also
• Short DFS and OS compared to other subtypes when treated
with conventional chemotherapy
• Chemotherapeutic agents may exhibit initial efficacy;
however, the development of resistance to therapy and
tolerability are concerns
• HER2 targeted therapy dramatically changed outcome
• Multiple agents available: questions about optimal
sequencing
2
Gradishar W. Curr Oncol Rep. 2011;13:11-16.

3. 3
Akt
SO
S
RA
S
RA
FME
K
VEG
F
MAP
K
P
P
P
P
Receptor-specific
ligands HER1, HER2,
HER3, or HER4
HER2
HER1
(EGFR)
HER2 HER4
HER3
Tyrosine kinase
domains
Plasma
membrane
PI3K
Cell proliferation
Cell survival
Cell mobility and invasiveness
Cytoplasm
Nucleus
Transcription
Signal Transduction by the HER Family
Promotes Proliferation, Survival, and
Invasiveness
Ross JS, et al. The Oncologist.

4. HER2+ Breast Cancer Subtypes
4
Breakdown of the
21% HER2+
Bauer K., Cancer. 2010;10:228.
ER+/PR+/HER2+
ER+/PR-/HER2+
ER-/PR+/HER2+
ER-/PR-/HER2+
0.5%
N=114,786
~21% HER2+
~79% HER2-
7.1%
10.8%
3.3%

5. Optimal Testing Algorithm
Immunohistochemistry (IHC)
Breast Cancer Specimen
(invasive component)
Equivocal for
HER2 protein
expression IHC 2+
Equivocal HER2 gene
amplification (Patients with
HER2/CEP17 ratio ≥2.0 were
eligible for the adjuvant
trastuzumab trials)
Positive for HER2
protein
expression IHC
3+ (defined as
uniform intense
membrane
staining of >30%
of invasive tumor
cells)
Negative for
HER2 protein
expression
IHC 0 or 1+
Negative for
HER2 gene
amplification
Positive for
HER2 gene
amplification
HER2 testing by
validated IHC assay
for HER2 protein
expression
Test with validated
assay for HER2 gene
amplification

6. HER2 Targeted Agents
Monoclonal Antibodies
• Trastuzumab
• Pertuzumab
• “Ado-Trastuzumab”
• Trastuzumab Deruxtecan
Tyrosine Kinase Inhibitors
• Lapatinib
• Neratinib
• Tucatinib
Trastuzumab
1998
Lapatinib
2007
Pertuzumab
2012
Ado Trastuzumab
2013
Neratinib
Feb 2020
Tucatinib
April 2020
Trastuzumab
Deruxtecan
Dec 2019

7. Trastuzumab
• Humanized monoclonal
antibody specific for
HER2
• Targets HER2 protein-
overexpressing cells
• Proposed MOA based
on preclinical studies
– Extracellular
– Intracellular
Dimerized HER2
receptors signal
tumor cells to
proliferate
Extracellular
trastuzumab
binds to subdomain IV of
HER2 receptors on
tumor cells, flagging
them for destruction by
the immune system
Intracellular
trastuzumab
blocks HER2
signaling to
inhibit
proliferation of
tumor cells
Arnould L, et al. Br J Cancer 2006;94:259-267. Bianco AR. J Chemother
2004;16(suppl 4):52-54.

8. Lapatinib
• Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 Blocks signaling
through EGFR and HER2
homodimers and heterodimer
– prevent signaling between
ErbB1/ErbB2 and other ErbB family members
• Binds reversibly to the cytoplasmic ATP-binding
site of the kinase, thereby preventing receptor
phosphorylation and activation
PTEN Lapatinib
P13K
pAkt
Ras
Raf
pErk
Shc
Grb2
So8
Phospholipid cell
membrane

9. Pertuzumab
By blocking HER2 dimerization, pertuzumab inhibits key HER signaling
Pertuzumab prevents the formation of HER2:HER3 receptor pairs
HER2
Dimerization
domain
Pertuzumab
HER3

10. T-DM1: Trastuzumab Emtansine
Adapted from LoRusso PM, et al. Clin Cancer Res. 2011;17:6437-6447.
Emtans
ine
release
Inhibition
of
microtubu
le
polymeriz
ation Internaliz
ation
HER2
T-DM1
Lysoso
me
Nucle
us
PP
P

11. Neratinib
• Neratinib is an oral, irreversible tyrosine kinase inhibitor of ERBB1, 2,
4 (HER1, 2, 4 receptors)
x

12. Tucatinib
tucatinib inhibits the phosphorylation of both HER-2 and HER-3, leading to
downstream changes in MAPK and AKT signaling and cell proliferation.

13. AC=doxorubicin (60mg/m2) [or epirubicin (75mg/m2)] + cyclophosphamide
(600mg/m2) q3w for 6 cycles;
Taxol (175mg/m2 x 3 h) q3w for 6 cycles; Herceptin (4mg/kg) loading dose, 2mg/kg qw
until progression;
No prior adjuvant AC Prior adjuvant AC
Taxol
(n=96)
Herceptin +
Taxol (n=92)
AC
(n=138)
Herceptin +
AC (n=143)
Stratify
Randomize Randomize
Slamon D, et al. N Engl J Med 2001;344:783.
n=469
MBC
HER2+
No prior CT for
MBC
Measurable disease
KPS 60%
First-line MBC: Schema
Slamon D, et al. N Engl J Med 2001;344:783.

14. DR=duration of response; H=Herceptin; ORR=overall response rate; T=Taxol;
TTP=time to progression;
m=months; Herceptin Package Insert 2002.
Subgroup Overall
Parameter H+AC
(n=143)
AC
(n=138)
H+T
(n=92)
T
(n=96)
H+CT
(n=235)
CT
(n=234)
ORR (%) 56 42 41 17 50 32
P value <0.02 <0.001 <0.001
Median DR (m) 9.1 6.7 10.5 4.5 9.1 6.1
P value 0.005 <0.01 <0.001
Median TTP (m) 7.8 6.1 6.9 3.0 7.4 4.6
P value <0.001 <0.001 <0.001
Median survival (m) 26.8 21.4 22.1 18.4 25.1 20.3
P value 0.16 0.17 0.046
Slamon D, et al. N Engl J Med 2001;344:783.
*
* Study was not powered to show a survival difference in subgroups.

15. HER2+ MBC
treated with
H based
regimen
atleast 6 wks
(N = 324)
Tab Lapatinib 1250mg
continuous
+Tab Capecitabine
2000mg/m2 D1-
D14(Q21)
Tab Capecitabine
2500mg/m2 D1-
D14(Q21)
R
Women with central nervous system (CNS)metastases were eligible if they were clinically
stable for at least 3 months after the discontinuation of corticosteroid and anticonvulsant
therapy.

17. HER2+ MBC
treated with
H based
regimen
(N = 291)
Tab Lapatinib
+Inj Trastuzumb
Tab Lapatibib
R
Median OS was 14 months for the combination therapy and 9.5 months for lapatinib
median PFS was 11.1 weeks with combination therapy compared with 8.1 weeks with
lapatinib only

19. Lapatinib along with Capecitabine is good option for her2 pos CNS mets patients
Phase 2
Can replace WBRT in Her 2 positive breast cancer with brain mets

20. HER2+
MBC
(prior
chemoth
erapy or
H)
Lapatinib+ capecitabine
Trastuzumab +
Capecitabine
R
Incidence of CNS metastases as first site of relapse
was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% for H+C arm

21. Phase III CLEOPATRA Study Design
First-Line Pertuzumab for MBC
HER2+
MBC
(N =
800)
Docetaxel 75 mg/m2*
q3wk
+ Trastuzumab 8 mg/kg,
→
6 mg/kg q3wk
+ PLACEBO
Docetaxel 75 mg/m2
q3wk +Trastuzumab 8
mg/kg, → 6 mg/kg
q3wk
+ Pertuzumab 840 mg
cycle 1, 420 mg q3wk
*Docetaxel can be increased to 100 mg/m2 q3wk if
tolerable.
Primary endpoint: PFS
90% of enrolled
patients
trastuzumab naïve
Baselga J, et al. N Engl J Med. 2012;366(2):109-119.
Swain SM, et al. N Engl J Med. 2015;372(8):724-734.
R

24. Grade ≥ 3 Events Placebo + Trastuzumab
+ Docetaxel
n = 396
Pertuzumab + Trastuzumab
+ Docetaxel
n = 408
Neutropenia 46.2% 49.0%
Febrile neutropenia 7.6% 13.7%
Leukopenia 14.9% 12.3%
Diarrhea 5.1% 9.3%
Peripheral neuropathy 1.8% 2.7%
Anemia 3.5% 2.5%
Asthenia 1.8% 2.7%
Fatigue 3.3% 2.2%
Granulocytopenia 2.3% 1.5%
Left ventricular dysfunction 3.3% 1.5%
Dyspnea 2.0% 1.0%
Hypertension 1.8% 2.0%
Pneumonia 2.0% 1.0%

25. T-DM1 vs Physician’s Choice –
Beyond Second-Line HER2 Therapy
(TH3RESA)
Krop IE, et al. Lancet Oncol. 2014;15(7):689-699.
Metastatic or
unresectable
locally advanced
HER2+ BC
Prior
trastuzumab,
taxane, and
lapatinib
(N = 602)
T-DM1
3.6 mg/kg IV every
21 days
n = 404
Physician’s choice: chemo,
hormone therapy, biologic, HER2-
targeted
n = 198
Primary Endpoints: PFS,
OS
R
2
1

26. PFS
198
404
120
334
62
241
28
114
13
66
6
27
1
12
0
0
TPC
T-DM1
Patients at risk:
Time, Months
1412108642
0.0
0.2
0.4
0.6
0.8
1.0
0
ProportionProgressionFree
Events,
n
Median,
Months
TPC
(n=198)
129 3.3
T-DM1
(n=404)
219 6.2
Stratified HR=0.528 (95% CI, 0.422-0.661)
P<0.0001

27. Final Overall Survival (OS) Analysis
Time, Months
ProportionSurviving
27
TPC
T-DM1
Patients at risk:
4034282216122
0.0
0.2
0.4
0.6
0.8
1.0
0 4 6 8 10 14 18 20 24 26 30 32 36 38
06396280107168198 150131122115 93 68 66 59 51 28 16 1 0
025132179226280388404 368347321298 251 207192 167164 84 54 12 2
Stratified HR=0.68 (95% CI, 0.54-0.85)
P=0.0007
(Prespecified crossing boundary: HR<0.748;
P<0.012)
Median, Months
TPC
(n=198)
15.8
T-DM1
(n=404)
22.7

28. Phase III Trial: T-DM1 vs Capecitabine
+ Lapatinib
EMILIA
Patients with HER2+
locally advanced or
MBC previously tx
with a taxane and
trastuzumab
(N = 980)
Trastuzumab-DM1
3.6 mg/kg q3wk
Continue until disease
progression or
unacceptable toxicity
occurs
Lapatinib
+
Capecitabine
Continue until disease
progression or
unacceptable toxicity
occurs
Verma S, et al. N Engl J Med.
Co-Primary Endpoints: OS and PFS
61% of patients in each group had 0-1 prior chemo regimens for locally advanced or metastatic disease.
39% had > 1 prior regimen.
R
TDM1 to be started if recurrence
in early stage within 6 months of
H based treatment

29. Median,
Months
Events, n
Cap + Lap 6.4 304
T-DM1 9.6 265
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
ProportionProgressionFree
Time, Months
Verma S, et al. N Engl J Med 2012;367:1783-1791 [including supplementary appendix].
Unstratified HR=0.66 (95% CI, 0.56-0.78; P<0.0001)
Median PFS by investigator review:
9.4 for T-DM1 vs 5.8 months for
Cap + Lap; HR=0.66; P<0.001
29
Stratified HR=0.65 (95% CI, 0.55-0.77)
P<0.001

30. Median No.
of Months
No. of Events
Lapatinib-Capecitabine 25.1 182
T-DM1 30.9 149
Stratified hazard ratio 0.68 95% CI [0.55-0.85]P < 0.001

31. EMILIA: Safety Profile
Capecitabine + Lapatinib
(n = 488)
T-DM1
(n = 490)
Adverse Event All Grades Grade ≥ 3 All Grades Grade ≥ 3
Diarrhea 80% 21% 23% 2%
Hand-Foot Syndrome 58% 16% 1% 0%
Vomiting 29% 5% 19% 1%
Hypokalemia 9% 4% 9% 2%
Fatigue 28% 4% 35% 2%
Nausea 45% 3% 39% 1%
Mucosal Inflammation 19% 2% 7% < 1%
Increased AST 9% 1% 22% 4%
Increased ALT 9% 1% 17% 3%
Thrombocytopenia 3% < 1% 28% 13%
Verma S, et al. N Engl J Med. Serious AE

32. Trastuzumab Deruxtecan– Beyond
Second-Line HER2 Therapy
(Destiny)
Krop IE, et al. Lancet Oncol. 2014;15(7):689-699.
Metastatic or
unresectable
locally advanced
HER2+ BC
Prior more tyan
2 lines of Her 2
targated
(N = 253)
Trastuzumab Deruxtecan
5.4 mg / kg
Q21 days
Primary Endpoints: PFS,
OS
2
1
Phase 2 single arm
Trastuzumab derux tecan, which was designed to improve on the critical attributes of
currently available antibody drug conjugates, has a higher drug-to-antibody ratio than
trastuzumab emtansine (8 vs 3)

33. •6.0% had a complete response,
•54.9% had a partial response.
•The median response duration was 14.8 months
• The median duration of progression-free survival was 16.4
months (95% CI, 12.7 to not reached) among all patients
•18.1 months (95% CI, 6.7 to 18.1) among the 24 patients who
were enroll as asymptomatic brain metastases

35. Metastatic or
unresectable
locally advanced
HER2+ BC
Prior Her 2 based
therapy
(N = 621)
neratinib (240 mg once
every day) plus
capecitabine (750
mg/m2 twice a day 14
d/21 d)
lapatinib (1,250 mg once every
day) plus capecitabine (1,000
mg/m2 twice a day 14 d/21 d)
R
Neratinib+ Capeciatabine vs Lapatinib +
Capecitabine > 2 HER2 Therapy
(NALA)

36. •Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95%
CI, 0.63 to 0.93; stratified log-rank P = .0059)
•OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098).
•Fewer interventions for CNS disease occurred with N+C versus L+C
(cumulative incidence, 22.8% v 29.2%; P = .043)
•median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33
to 0.74; P = .0004)
•The most common all-grade adverse events were diarrhea (N+C 83% v L+C
66%) and nausea (53% v 42%).
Neratinib+ Capeciatabine vs Lapatinib +
Capecitabine > 2 HER2 Therapy
(NALA)

37. NEfERT-T Neratinib in HER2+ MBC
Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel
and 12.9 months (95% CI, 11.1-14.8) in H+T arm
With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower
(relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases
delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004).
Increased incidence of Diarrhea in Neratinib arm

38. Metastatic or
unresectable locally
advanced HER2+ BC
Prior Her
(Trastuzumab/Pertuz
umab/TDM1)therapy
(N = 612)
Tucatinib (300 mg orally twice
daily),+trastuzumab +capecitabine
(1000 mg m2 BD D1 –D14 q21)
Placebo+ Trastuzumab
+capecitabine
(1000 mg m2 BD D1 –D14 q21)
R
2:1
Tucatinib + Trastuzumab+ Capecitabine vs
Placebo+Trastuzumab + Capecitabine > 2 HER2 Therapy
(Her2CLIMB)
Patients with brain metastases were included unless they were in need of immediate
local intervention, in which case they could receive local therapy
More than one third having brain mets (46% vs 44%)

43. Received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy
Randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI.
Patients for whom chemotherapy was intended were excluded (Low burden of disease,
elderly, already received multiple line chemo before)
LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months

44. HER2+ MBC were randomized 1:1 to receive either P+T alone (arm A) or P+T combined
with weekly paclitaxel or vinorelbine (arm B)
followed by maintenance treatment with T+P until progression. After progression, T-DM1
was given as second line therapy in both arms

46. HOW TO SEQUENCE
ESMO

47. TAXANE OR VINORELBINE IN 1ST LINE CHEMO WITH TRASTUZUMAB AND
ON PROGRESSION GEMCITABINE , CAPECITABINE , ERIBULIN, PLATINUM

48. •contraindications to ChT,
•patients with a strong preference against ChT or those with a long disease-free interval
•minimaldisease burden (in particular in terms of visceral involvemenT
•strong ER/progesterone receptor (PgR) expression
ER/PR & HER2NEU POSITIVE

49. Practical consensus recommendations regarding the management of HER2 neu positive metastatic breast cancer M. Basade etal
INDIAN CONTEXT

50. CONCLUSION
•Choice of the anti-HER2 will depend on country-specific
availability, the specific anti-HER2 therapy previously administered
• MBC denovo should be started with trastuzumab pertuzumab
and docetaxel based chemotherapy
•In 2nd line Trastuzumab Emtansine is ideal
•In 3rd line Lapatinib + Capeciatabine or Trastuzumab Duraxetine
/Neratinib/Tucatinib
•In brain mets TKI should be used as better BBB penetration
•Cardiac toxicity monitoring periodically
•Economic toxicity should be taken in account