Her2. dr

CANCER DE MAMA
HER 2+

Dr. Luis Miguel Zetina Toache
Cancer Consultants GT

Trastuzumab:

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.

Novel anti-HER2 therapies:

Baselga J Ann Oncol 2010;21:vii36-vii40

HER pathways are of critical
importance in cancer

“Beginning with benign hyperplasia and extending through
invasive metastasis, a number of studies demonstrate
that [HER family] receptor activation can play a major role
in all aspects of cancer development.”
— Sliwkowski MX, ―Alterations in the ErbB
Signaling Network in Breast Cancer‖1

1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2004:415-426.

Structure of a HER family receptor1

HER family receptors exist on
the surface of cells and contain
extracellular, transmembrane,
and tyrosine kinase domains.

Each of these domains is
responsible for a different aspect
of HER signaling pathways1

1. Burgess AW, Cho HS, Eigenbrot C, et al.
Mol Cell. 2003;12:541-542.

Components of HER family receptors

Activation of HER receptors has numerous
cellular effects and is a complex process

Receptor activation is a complex, multistep process
Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM.
Copyright © 2000 J Cell Phys; Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

1. Ménard S, Tagliabue E, Campiglio M, Pupa SM. J Cell Phys. 2000;182:150-162. 2. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK,
eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426. 3. Olayioye MA, Neve RM, Lane HA, Hynes NE. EMBO
J. 2000;19:3159-3167.

Signal Transduction by the HER Family Promotes
Proliferation, Survival, and Invasiveness

Receptor specific
ligands HER2 HER1, HER2,
HER3 HER3*, or HER4
HER4
HER2
VEGF
HER1
(EGFR)

Plasma
PI3K P SOS
P
membrane
Tyrosine kinase
domains P RAS
Akt
RAF
MAP
K
P
MEK

Cytoplasm
Cell proliferation
Cell survival
Cell mobility and invasiveness
Nucleus
Transcription

Adapted from Hudis. N Engl J Med. 2007;357:39

Receptor regulation through
internalization

Receptor internalization is an
important regulator of HER family
signaling in normal cells, and is
retained in cancerous cells1

: 1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow
M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Adapted with permission from Lippincott Williams & Wilkins. Sliwkowski MX. In: Harris JR,
Philadelphia, PA: Lippincott Williams & Wilkins; Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA:
2004:415-426. Lippincott Williams & Wilkins; 2004:415-426.

HER2 Overexpression in Breast Cancer

HER2 is overexpressed in
~ 25% of breast cancers

Normal (1x)
~ 25,000-50,000 HER2
receptors

Overexpressed
HER2 (10-100x)
up to ~ 2,000,000
HER2 receptors

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Excessive cellular division
Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.
Slamon DJ, et al. Science. 1987;235:177-182.

HER2 Overexpression Shortens Survival

HER2 oncogene
amplification

HER2 oncoprotein
overexpression

Shortened survival
Median Survival From First Diagnosis
HER2 overexpressing 3 years
HER2 normal 6-7 years

TRATAMIENTO DE
CÁNCER DE MAMA
HER 2 POSITIVO

Estimación de las recurrencias prevenidas por el
uso de trastuzumab en EBC en USA
(M Danese; SABCS 08 poster 2107)

• Los datos del SEER estiman que Trastuzumab adyuvante
previene 2,800 recurrencias en 1 año en USA
• Extrapolado en un período de 25 años podría prevenir
más de 50,000 recurrencias
• Estos resultados son consistentes con los europeos de
Weisgerber-Kriegl presentados en ASCO 2008

PILAR DE TRATAMIENTO PARA PTES HER 2 POSITIVAS

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
Trastuzumab: Mecanismo de accion

Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654

Estudios de Herceptin en Adyuvancia:
>13,000 pacientes tratados
HERA (ex-USA) BCIRG 006 (global)
Observación
IHC / FISH FISH
1 año
(n=5090) (n=3222)
1 año
2 años

1 año

NCCTG N9831 (USA) NSABP B-31 (USA)

IHC / FISH IHC / FISH
1 año
(n=3505) (n=2030)
1 año
1 año

Quimioterapia Doxorubicina + Docetaxel +
ciclofosfamida Docetaxel carboplatino Herceptin Paclitaxel
estándar

Piccart-Gebhart et al 2005;
FISH, hibridización fluorescente in situ Romond et al 2005; Slamon et al 2006

Análisis combinado de NCCTG N9831
actualizado / NSABP B-31: Beneficio de DFS*

Pacientes (%) 100
92.3%
87.9% 85.9%
80
86.4% 52%
77.6%
73.1%
60

Seguimiento medio: 2.9 años
40
n Eventos
ACPH 1989 222
20 ACP 1979 397
HR=0.48; p 0.00001
Años desde la
0 randomización
0 1 2 3 4 5 6 7
No. 1854 1347 868 522 202 4
at risk 1800 1235 753 460 168 8

*Eventos intención de tratamiento: enfermedad recurrente,
cáncer de mama contralateral, muerte por 2ndo primario. Perez et al 2007
DFS: sobrevida libre de enfermedad

Actualización de NCCTG N9831 / NSABP B-31
– análisis combinado: beneficio de OS*

Pacientes (%) 100 97.5%
94.6% 92.6%
95.9%
92.7%
89.4%
80
35%
60

40
n
ACPH 1989
20 ACP 1979
HR=0.65; p=0.0007
Años desde la
0 randomización
0 1 2 3 4 5
No. 1886 1419 938 570 217
at risk 1863 1376 898 562 211

*Eventos intención de tratamiento: enfermedad recurrente, cáncer de
mama contralateral, 2ndo primario, muerte Perez et al 2007

Estudios de Herceptin adyuvante:
beneficio en DFS probado

Seguimiento medio a
2 años
HERA H 1 año 2

B-31 / N9831 ACPH 4

BCIRG 006 ACDH 3

BCIRG 006 DCarboH 3

FinHer VH / DHa 3

0 1 2
Favorece a No favorece
Herceptin a Herceptin
HR
V, vinorelbina Joensuu et al 2006; Perez et al 2007;
aSobrevida libre de recaída Slamon et al 2006; Smith et al 2007

Estudios de Herceptin adyuvante:
beneficio de OS probado

Seguimiento medio en
años
HERA H 1 año 2

B-31 / N9831 ACPH 4

BCIRG 006 ACDH 3

BCIRG 006 DCarboH 3

FinHer VH / DHa 3

0 1 2
Favorece a No favorece a
Herceptin Herceptin
HR
Joensuu et al 2006; Perez et al 2007;
Slamon et al 2006; Smith et al 2007

Conclusions:
The addition of 1 year of adjuvant trastuzumab significantly improved disease-
free and overall survival among women with HER2-positive breast cancer. The
risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus
trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of
cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-
006 ClinicalTrials .gov number, NCT00021255.)

Table 2. Therapeutic Index for Critical Clinical Events.*
AC-T plus
Clinical Event AC-T Trastuzumab TCH
number of events
Total events 201 146 149
Distant breast-cancer recurrence 188 124 144
Grade 3 or 4 congestive heart failure 7 21 4
Acute leukemia 6 1 1†

D. Slamon
New England Journal of Medicine
october 6, 2011 vol. 365 no. 14

Estudio internacional, fase III,
randomizado en CMLA: NOAH

CMLA HER2-positivo CMLA HER2-negativo
(IHC 3+ or FISH+) (IHC 0/1+)

n=115 n=113 n=99
H + AP AP AP
c3s x 3 ciclos c3s x 3 ciclos c3s x 3 ciclos

H+P P P
c3s x 4 ciclos c3s x 4 ciclos c3s x 4 ciclos

H c3s x 4 ciclos CMF CMF
+ CMF c4s x 3 ciclos c4s x 3 ciclos c4s x 3 ciclos

Cirugía seguida de Cirugía seguida de Cirugía seguida de
radioterapiaa radioterapiaa radioterapiaa

H continuada c3s
hasta la semana 52

AP, doxorubicina (60 mg/m2), paclitaxel (150 mg/m2); CMF, ciclofosfamida, metotrexate, fluorouracilo; H, Herceptin (8 mg/kg dosis
de carga, luego 6 mg/kg);
CMLA: cáncer de mama localmente avanzadolocally; P, paclitaxel (175 mg/m2); Gianni et al 2007
aPacientes positivos por receptor hormonal recibirán tamoxifeno adyuvante

Herceptin neoadyuvante duplica
la tasa de respuesta patológica

Pacientes 50 p=0.002
(%) p=0.003
40 43
38
p=0.29
30 p=0.43

20 23
20
17 16
10

0
Con H Sin H HER2 Con H Sin H HER2
negativo negativo
HER2 positivo HER2 positivo

pCR tpCR

tpCR: total pCR en mama y ganglios Gianni et al 2007

Y los tumores menores de 2 cms, ganglios (-) ?

High Risk of Recurrence for Breast Cancer Patients with HER2-Positive Node Negative
Tumors 1 cm or Smaller

HER2-positive (%) HER2-negative (%) P value

5-yr RFS 77 94 <0.001

Gonzalez-Angulo AM, et al. J Clin Oncol 2009;27(34):5700-6


Case 1: Woman With MBC and No
Previous Trastuzumab
 Presentation: 58-yr-old woman was found to have
architectural distortion in the right breast, upper outer
quadrant, on routine screening mammography
– Core needle biopsy confirmed invasive ductal carcinoma,
estimated by imaging to be a T1 lesion
 Treatment: She underwent lumpectomy/SLNB that
revealed a 0.9-cm intermediate-grade invasive ductal
carcinoma that was ER+/PgR+/HER2+ by FISH, with a
Ki-67 value of 30%
– 2 sentinel nodes were removed and found to be uninvolved
by cancer
T1 NO MO G2 ER/PR+ HER2+


 Follow-up: She received adjuvant radiation therapy followed by
letrozole for 1 yr, at which time she was seen by her oncologist for
new cough and mild shortness of breath
– CT scan of the chest revealed a mild right pleural effusion and several
nodules up to 1 cm in size in the right, middle, and lower lobes

– Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC,
consistent with breast primary

– No other metastases were detected by CT or bone scan

 There are no clinical trials available at your center for which she is
eligible. You review multiple treatment options with her and she tells
you she would like to take the treatment that has the highest chance of
leading to a response and to a prolonged survival, as she recently
found out her daughter is pregnant with her first grandchild



What treatment option would you recommend at this time?
A. Trastuzumab plus chemotherapy
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent


A. Trastuzumab plus chemotherapy (preferred choice)
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent

Single-Agent Trastuzumab in First-line
Treatment of HER2+ MBC
Patients Response Rate, % Median Time to
Progression, Mos
HER2+ by IHC 26 3.5
(N = 111)
HER2+ by FISH 34 4.9
(n = 79)

Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.

Herceptin Combinations as First-line
Therapy for MBC: Pivotal Phase III Trial

Paclitaxel
Previous (n = 96)
Patients with adjuvant
HER2+ (IHC 2+/3+) AC Herceptin
MBC, no previous + Paclitaxel
chemotherapy, (n = 92)
measurable
disease, KPS ≥ 60% AC
No previous (n = 138)
(N = 469) adjuvant
AC Herceptin
+ AC
(n = 143)

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

Herceptin in MBC: The Pivotal Trial

Treatment Objective Median TTP, Mos Median OS, Mos
Response Rate, %
Chemo 32 4.6 20.3
Chemo + 50 7.4 25.1
Herceptin

P < .001 for all 3 comparisons.
Despite crossover at TTP

Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

Herceptin in Triple-Combination
Regimens: Response Rates

Yardley et al, 2004 (N = 24) H+V+T
Untch et al, 2004 (N = 25) H + E90 + C
Untch et al, 2004 (N = 26) H + E60 + C
Dirix et al, 2006 (N = 34) H + Carbo + T
Chan et al, 2007 (N = 34) H+V+X
Fountzilas et al, 2004 (N = 40) H+G+P
Yardley et al, 2006 (N = 41) H + G + Carbo
Miller et al, 2002 (N = 45) H+G+P
Venturini et al, 2006 (N = 45) H+E+T
Perez et al, 2005 (N = 43) H + Carbo + P every 3 wks
Perez et al, 2005 (N = 48) H + Carbo + P every wk
Cortes et al, 2004 (N = 54) H + TLC D-99 + P
Yardley et al, 2002 (N = 61) H + Carbo + T
Pegram et al, 2004 (N = 59) H + Carbo + T
Pegram et al, 2004 (N = 62) H + Cisplatin + T
Robert et al, 2006 (N = 92) H + Carbo + P
Wardley et al, 2006 (N = 111) H+X+T
Forbes et al, 2006 (N = 130) H + Carbo + T

0 10 20 30 40 50 60 70 80 90 100
ORR (%)

Herceptin in Recommended First-line
Combinations for HER2+ MBC
HER2+ disease without previous Herceptin: Herceptin plus
• Paclitaxel ± carboplatin

• Docetaxel

• Vinorelbine

• Capecitabine

HER2+ disease with previous Herceptin: Herceptin plus
• Other first-line agents

• Capecitabine

• Lapatinib (without cytotoxic therapy)

NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.

Cross-talk Between Signal
Transduction and Endocrine Pathways
Growth Factor IGFR
Estrogen
EGFR/HER2

MoAb
Plasma P P
Membrane P P

P SOS
P
P13-K RAS
RAF
AI Cell
Survival P
Akt MEK
P
ER
p90RSK MAPK
P P

Cytoplasm Cell
P P P Basal
P Transcription Growth
ER p160 CBP Machinery
ER

Nucleus ERE ER Target Gene Transcription

Adapted from Johnston SRD. Clin Cancer Res. 2005;11:889s-899s.

Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant
breast cancer, with opportunities for targeted intervention.

Johnston S R Clin Cancer Res 2010;16:1979-1987

©2010 by American Association for Cancer Research

Hormonal Therapy in HER2+
MBC

Regimen ORR, % PFS, Mos
Trastuzumab (N = 79)[1] 26 3.5-3.8
Anastrozole + trastuzumab (N = 103)[2] 20 4.8
Anastrozole (N = 104)[2] 7 2.4
Lapatinib + letrozole (N = 642)[3] 28 8.2
Letrozole (N = 644)[3] 15 3.0
Lapatinib (N = 138)[4] 24 NA

1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.
2. Mackey JR, et al. SABCS 2006. Abstract 3.
3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.
4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.


Lapatinib Blocks Signaling Through
Multiple Receptor Combinations
 Blocks signaling through 1+1 2+2 1+2
ErbB1 and ErbB2 homodimers
and heterodimers
 Might also prevent signaling
through heterodimers between
these receptors and other ErbB
family members
 Potentially blocks multiple ErbB
signaling pathways

Downstream signaling
cascade
Lapatinib is indicated in MBC only for patients with progression
after trastuzumab, anthracycline, and taxane treatment


Lapatinib as First-line Treatment for HER2-
Amplified LABC or MBC
 Patients (N = 138) randomized to 2 schedules of lapatinib
monotherapy
Endpoint Lapatinib Lapatinib All Patients
1500 mg/day 500 mg BID (N = 138)
(n = 69) (n = 69)
Response rate, n (%) 15 (22) 18 (26) 33 (24)
Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31)
6-mo PFS, % 41 45 43

 Median time to response (all patients): 7.9 wks; median duration
of response (all patients): 28.4 wks
 Safety: only grade 1/2 asymptomatic cardiac adverse events
(4 patients)
Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.

Current therapeutic cascade in HER2+ MBC
HER2+ /ER +
MBC

Good performance status Poor performance status
Visceral disease Non visceral disease
Rapidly progressing Slow progression

Prior A.I.?

YES NO

Herceptin + Herceptin Herceptin +
Chemotherapy monotherapy Aromatase
Inhibitor

Tratamiento mas allá de progresión


Case 2: Woman With HER2+ MBC and
Progression Following Trastuzumab
 Background: 39-yr-old woman diagnosed with stage IIA, breast cancer
in 2004. T2 N0 MO
– 2.6-cm tumor

– ER+/PgR-/HER2+

 Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen
 Follow-up: 1 yr after end of chemotherapy, she is found to have bone
and lymph node metastases
– Lymph node biopsy reveals the tumor is negative for hormone receptors
(ER/PgR) and continues to overexpress HER2

 Treatment: she receives 6 cycles of TCH and achieves CR
– She continues on maintenance single-agent trastuzumab without
progression for almost 2 yrs


Scans reveal new liver metastases, and vinorelbine is added
to trastuzumab. She has another CR that lasts 9 mos, at
which time scans reveal progressive disease in the liver and
bones.
A. Switch to lapatinib/capecitabine
B. Switch to lapatinib/trastuzumab
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone


Scans reveal new liver metastases, and vinorelbine is added
to trastuzumab. She has another CR that lasts 9 mos, at
which time scans reveal progressive disease in the liver and
bones.
A. Switch to lapatinib/capecitabine (preferred choice)
B. Switch to lapatinib/trastuzumab (reasonable)
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone


Mechanism of Action of Lapatinib
Compared to Trastuzumab
Trastuzumab
T

1 1 2 2 1 2

Erb
receptors
L L L L L L Lapatinib

Downstream signaling pathways
Cell proliferation Cell survival


EGF100151 Phase III Study: Lapatinib +
Capecitabine in Advanced Breast Cancer
Lapatinib
1250 mg/day PO +
Capecitabine
Patients with HER2+ 2000 mg/m2/day on
progressive MBC or Days 1-14 every 21 days
stage IIIB/IIIC LABC with
T4 lesion and unlimited Capecitabine
previous therapies* 2500 mg/m2/day on
Days 1-14 every 21 days
 Primary endpoint: TTP
 Secondary endpoints: OS, PFS, ORR

*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or
adjuvant).

Geyer C, et al. N Engl J Med. 2006;355:2733-2743.


Lapatinib + Capecitabine in HER2+ MBC:
TTP
TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab
Cumulative Progression Free (%)

Cumulative Progression Free (%)
100 100 Regimen

80 80
Capecitabine Capecitabine
Lapatinib + capecitabine Lapatinib + capecitabine
60 60

40 40

20 20

0 0
0 20 40 60 80 0 20 40 60 80
Wks Wks

Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced
breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed
through Copyright Clearance Center, Inc.

Cameron D, et al. Oncologist. 2010;15:924-934.


Lapatinib + Capecitabine in HER2+ MBC:
Efficacy
Result Capecitabine Capecitabine + HR P Value
(n = 201) Lapatinib
(n = 207†)
Median TTP, wks[1] 18.6 31.3 0.50 < .001
OS, wks[1] 56.6 71.4 0.79 .077
ORR, %[2] 13.9 23.7 -- .017
Brain mets as site of first 13 (6) 4 (2) -- .045
progression,* n (%)[2]
† n=198 in 2008 study.
*Exploratory analysis.

1. Cameron D, et al. Oncologist. 2010;15:924-934
2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.


Combining Lapatinib and Trastuzumab
Increases Antitumor Activity
1600  Treatment with lapatinib plus
Tumor Volume (mm3)

1400
trastuzumab resulted in complete
1200 Control
Trastuzumab
tumor remission in mouse model
1000
800 Lapatinib
* Trastuzumab + lapatinib – Effect was durable: no tumor relapse
600 † observed at 8 mos after treatment
*
400
†‡ †
200  Lapatinib induced accumulation of
0
13
16 19 21 23 inactive HER2 at plasma membrane
Days After Injection
*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; – Trastuzumab-mediated cytotoxicity
P < .01 vs both lapatinib and trastuzumab. was higher with the addition of
lapatinib in MCF7/HER2 cells

 In vivo activity was consistent with in
vitro data demonstrating the
combination as synergistic
Scaltriti M, et al. Oncogene. 2009;28:803-814.
Reprinted by permission from Macmillan Publishers Ltd: Konecny GE, et al. Cancer Res. 2006;66:1630-
Oncogene; Scaltriti, et al. 28:803-814, copyright 2009. 1639. Xia W, et al. Oncogene. 2004;23:646-653.

EGF104900 Estudio fase III: Bloqueo dual
de Her2 en CMM

Lapatinib 1500 mg/day PO
Patients with HER2+
(n = 148)
(FISH/IHC3+) MBC and
progression on
anthracycline, taxane, and Lapatinib 1000 mg/day PO +
Herceptin Herceptin 4 mg/kg → 2 mg/kg IV weekly
(n = 148)

 Objetivo primario: supervivencia libre de progresión

 Objetivos secundarios: Supervivencia global, respuesta, beneficio clínico

Blackwell KL, et al. J ClinOncol. 2010;28:1124-1130.

EGF104900 Estudiofase III:
Bloqueo dual de Her2 en CMM

100 L L+T
Supervivencia
(n = 145) (n = 146)
80% Muertes, n (%) 113 (78) 105 (72)
80
Mediana (m) 9.5 14
Supervivencia global

HR (95% CI) 0.74 (0.57-0.97)
56%
60 70% Log-rank P value .026

6 meses SG
40
41%
L 12 meses SG
20 L+T

0
0 5 10 15 20 25 30 35
Pacientes en riesgo, n Meses desde la aleatorización
L 148 121 88 64 43 25 1
L + T 148 102 65 47 28 13
Blackwell KL, et al. SABCS 2009. Abstract 61.


Relapse Following Trastuzumab/Lapatinib
 Presentation: 56-yr-old woman was diagnosed with stage III ER+/
PgR-/HER2+ breast cancer
– Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab

 Follow-up: 3 yrs after completing maintenance trastuzumab, she was
diagnosed with bone and lung metastases
– Treatment: docetaxel/trastuzumab

 Follow-up: after achieving PR that lasted for 9 mos, she developed
liver metastases
– Treatment: lapatinib/capecitabine

 Follow-up: she achieved SD for 6 mos, after which she developed
lung and lymph node metastases


What treatment options do you feel are appropriate to
consider for this patient at this time?
A. Lapatinib/trastuzumab
B. Enrollment in a trial evaluating a new agent for HER2+ breast
cancer
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy


What treatment options do you feel are appropriate to
consider for this patient at this time?
A. Lapatinib/trastuzumab (reasonable)
B. Enrollment in a trial evaluating a new agent for HER2+ breast
cancer (preferred choice)
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy (reasonable)

Can we further optimise the treatment of
HER2-positive MBC in the future?

Despite the proven efficacy of the standard of care, Herceptin plus
chemotherapy, a proportion of patients with HER2-positive breast
cancer will not respond, while the majority of patients with MBC will
progress within 1 year1

1. Slamon et al. New Eng J Med 2001; 344:783–792
MBC = metastatic breast cancer

Pertuzumab

Mechanism of action

There are four receptors in the HER family

HER1/EGFR HER2 HER3 HER4

• Receptors are able to homo- and heterodimerise
• HER2 does not appear to have a direct ligand and HER3 lacks kinase activity
• However, HER2 and HER3 are highly complementary to each other

EGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137

HER2:HER3 dimers initiate the strongest
mitogenic signalling

Homodimers Heterodimer
s
HER1:HER2 HER1:HER3
HER4:HER4 HER1:HER4
HER3:HER3 HER2:HER3
HER2:HER2 HER2:HER4
HER1:HER1 HER3:HER4

+ + + + + + + +
+ + + +
+ + + +
Signalling activity +
Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.

HER2 dimerises preferentially with HER3 to drive
downstream signalling
HER2 HER3

Ligand-activated
HER2:HER3 dimer

P
P
P P

Phosphorylation of the HER3 intracellular domain by HER2
initiates a signalling cascade

Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137;
Graus-Porta et al. EMBO J 1997;1647–1655; Tzahar et al. Mol Cell Biol 1996;16:5276–5287;
Lee-Hoeflich et al. Cancer Res 2008;68:5878–5887.

HER2:HER3 dimerisation initiates multiple signalling
pathways, including increased tumour cell proliferation

HER2 HER3

RAS Sos GRb
2 Shc
PI3K
P PP
P P P

Akt
PDK
RAF P
1
Downstream PI3K/Akt signalling is GSK36
mainly mediated by HER3 after MEK
mTOR
NF B
Cyclin 01 BAD
transphosphorylation by HER2 p27

Apoptosis
MAPK
P
P

Cell cycle Survival
control

Angiogenesis Proliferation

Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127–137; Olayioye et al. EMBO J 2000;19:3159–3167;
Kim et al. J Biol Chem 1994;269:24747–24755; Soltoff et al. Mol Cell Biol 1994;14:3550–3558;
Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Rowinsky. Annu Rev Med 2004;55:433–457;

Pertuzumab is the first in a new class of targeted
anticancer therapeutic agents called HER2 Dimerisation
Inhibitors

• By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate
cancer cell proliferation and survival1–4
• Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5

HER2 HER3

Pertuzumab
Dimerisation
domain

1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95;
3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328;
5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892

Herceptin and pertuzumab bind to different epitopes on
HER2 and show complementary mechanism of actions

Pertuzumab
Herceptin HER2
HER3

Dimerisation
domain
Subdomain IV
• Herceptin does not inhibit ligand- • Pertuzumab inhibits ligand-activated
activated HER2 dimerisation HER2 dimerisation
• Herceptin prevents HER2 activation by • Pertuzumab flags cells for destruction
extracellular domain shedding by the immune system
• Pertuzumab suppresses multiple HER
• Herceptin inhibits ligand-independent signalling pathways, leading to a more
HER2 signalling and flags cells for comprehensive blockade of HER2-driven
destruction by the immune system signalling
Cho et al. Nature 2003;421:756–760; Fendly et al. Cancer Res 1990;50:1550–1558; Franklin et al. Cancer Cell 2004;5:317–328;
Nahta et al. Cancer Res 2004;64:2343–2346; Scheuer et al. Cancer Res 2009;69:9330–9336

Pertuzumab

HER2-positive MBC
combination studies

Summary of pertuzumab combination
trials in HER2-positive breast cancer

EBC First-line MBC Second-line MBC Third-line MBC
(Neo-adjuvant)

NEOSPHERE
CLEOPATRA PHEREXA
(n=400)
(n=800) (n=450)
D+T vs D+T+P vs
D+T±P Capecitabine+T±P
T+P vs D+P

TRYPHAENA
(n=225) BO17929 cohorts 1+2 (n=66)
D+FEC+T+P vs P+T
carboplatin+D+T+P BO17929 cohort 3 (n=29)
P mono then P+T

NCI study (n=11)
Enrolment complete
P+T
Enrolling

D = docetaxel; EBC = early-stage breast cancer;
FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic
breast cancer; Data on file. Genentech USA, Inc., CA, USA and
P = pertuzumab; T = Herceptin F Hoffmann-La Roche Ltd., Basel, Switzerland

Trastuzumab-DM1 (T-DM1)
is a first-in-class antibody drug-conjugate (ADC)

Aim for paradigm shift in treatment of breast cancer

Providing greater efficacy and better tolerability than Herceptin plus
chemotherapy
as single agent or in combination with a biologic

“… replacing Herceptin plus chemotherapy”

74

Anatomy of T-DM1

75

T-DM1 selectively delivers a highly toxic
payload to HER2-positive tumor cells

• Trastuzumab-like activity by binding to HER2 to the HER2 protein
T-DM1 binds
on cancer cells
• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1

Receptor-T-DM1 complex is
Potent antimicrotubule
internalized into HER2-positive
agent is released once inside
cancer cell
the HER2-positive
tumor cell

TDM4450g: ongoing Phase II study of T-DM1 vs
trastuzumab + docetaxel in first-line HER2-positive
MBC

Primary endpoints
HER2-positive MBC
• PFS (independent No prior chemotherapy for MBC
assessment) (n=137)
• Safety
Secondary endpoints
• OS
• ORR
• DoR Trastuzumab +
T-DM1
• CBR docetaxel
• Pharmacokinetic
properties Fully recruited, results to be
• Time to symptom presented later this year
progression

PI: Edith Perez Clinicaltrials.gov

• Se observó una mejora significativa de la SSP en las pacientes del grupo de trastuzumab emtansina (n
= 67) en comparación con el grupo de Herceptin + quimioterapia (n = 70), (mediana de SSP: 14,2
meses frente a 9,2; HR: 0,59; p: 0,035).
• La TRO fue mayor en el grupo de trastuzumab emtansina que en el de Herceptin + quimioterapia
(64,2% frente al 58,0%).
• Los eventos adversos (EA) frecuentes y graves (grado 3 o superior) disminuyeron significativamente
en el grupo de trastuzumab emtansina en comparación con el grupo de Herceptin + quimioterapia:
Los EA más frecuentes en el grupo de trastuzumab emtansina fueron fatiga (49,3%), náuseas (47,8%),
un aumento de las cifras de una enzima específica secretada por el hígado y otros órganos (aspartato
aminotransferasa o AST, 39,1%) y fiebre (39,1%). Los EA más frecuentes en el grupo de Herceptin +
quimioterapia fueron pérdida de cabello (66,7%), una cifra reducida de un tipo específico de
leucocitos (neutropenia, 63,6%), diarrea (45,5%) y fatiga (45,5%). Coincidiendo con resultados ya
publicados, EA graves (grado 3 o superior) se notificaron con menor frecuencia en el grupo de
trastuzumab emtansina que en el de Herceptin + quimioterapia (46,4% frente a 89,4%), al igual que
suspensiones del tratamiento por EA (7,2% frente a 28,8%). Los EA graves más frecuentes en el grupo
de trastuzumab emtansina consistieron en una cifra aumentada de dos enzimas hepáticas diferentes
(ALT y AST) y una cifra baja de plaquetas (8,7%). Los EA graves más frecuentes en el grupo de
3/5
Herceptin + quimioterapia consistieron en una cifra reducida de un tipo específico de leucocitos
(neutropenia, 60,6%), una cifra total reducida de leucocitos (leucocitopenia, 25,8%) y fiebre asociada
con una cifra reducida de un tipo específico de leucocitos (neutropenia febril, 13,6%).
• Los datos de la supervivencia global no están maduros en este momento. El número de fallecimientos
en cada grupo del estudio fue idéntico. Según los investigadores, ninguna muerte estaba relacionada
con el tratamiento (trastuzumab emtansina o Herceptin + quimioterapia).

TDM4370g (EMILIA): ongoing Phase III study of T-DM1 vs
capecitabine + lapatinib in the second-line setting

Primary endpoints
HER2-positive incurable locally advanced
● PFS (independent assessment) breast cancer or MBC
● Safety Prior trastuzumab and / or taxane
Secondary endpoints (n=580)
● OS
● PFS (investigator assessment)
● ORR
● CBR
● DoR Capecitabine +
T-DM1
lapatinib
● Quality of life
● TTF
n=319 as of June 4, 2010
200 sites
FPI: February 27 2009

TTF, time to treatment failure
FPI, first patient in Clinicaltrials.gov

TDM4788g/BO22589 (MARIANNE): first-line
T-DM1 + pertuzumab vs trastuzumab + docetaxel

Primary endpoints
● PFS (independent assessment) HER2-positive MBC
No prior chemotherapy
● Safety (n=1092)
Secondary endpoints
● ORR (independent assessment)
● OS
● 1-year survival
● PFS
Trastuzumab T-DM1 + T-DM1 +
● ORR (investigator assessment)
+ taxane pertuzumab placebo
● CBR
● TTF
Global study starts summer 2010
● DoR
332 centers in 40 countries
● Safety and tolerability

Clinicaltrials.gov

T-DM1 and Pertuzumab: Binding to
HER2

Pertuzumab-HER2 Complex Herceptin/T-DM1-HER2 Complex
Pertuzumab

I I Dimerization domain

II II Herceptin/T-DM1
III III

IV IV

Diéras V, et al. SABCS 2010. Abstract P3-14-01.

T-DM1 and Pertuzumab: Mechanism of Action

Pertuzumab HER2 Dimer
T-DM1
HER2

Lysosome
DM1

Nucleus

Diéras V, et al. SABCS 2010. Abstract P3-14-01.


mTOR Inhibition May Overcome
Trastuzumab Resistance
IGF-1R
Increased signaling through IGF-1R
EGFR/HER2
Nutrients

Truncated HER2
PI3K

PTEN Constitutive PI3K/AKT activation
LKB1
AKT
Absent or low PTEN
AMPK
TSC1 TSC2
Elevated AKT or pAKT
RHEB

Growth & mTOR mTOR inhibitor
proliferation  Downstream inhibition with mTOR inhibitor
counters these resistance mechanisms
 Synergy of mTOR inhibition and
trastuzumab in vitro and in vivo
Angiogenesis Cell
metabolism

Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.
Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.


Angiogenesis in MCF-7 Spheroids: Day 14

MCF-7 Neo:
3.5 x mag.
 Mature vasculature
 No vessel buds
 Development stopped

MCF-7 HER-2/neu:
10 x mag.
 High number mature vessels
 Vessel buds in center of tumor
 Vasculature still growing


Targeted Agents for HER2+ Breast Cancer
Trastuzumab
Bevacizumab
phase III VEGF T-DM1
phase III
Sunitinib EGFR Pertuzumab
phase II
VEGFR HER2 phase III
P P P P

P P PI3-K P P
Akt/PKB

Lapatinib
PTEN phase III
Everolimus
phase III mTOR Neratinib
phase III
4E-BP1

S6K1 Gefitinib
elF-4E
phase II
Protein synthesis
Cell growth, proliferation, survival, metastasis, angiogenesis

Muchisimas
Gracias

Dr. Luis Miguel Zetina Toache
Cancer Consultants GT

Her2. dr

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