An Update on Breast Cancer

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TRASTUZUMAB EN ADYUVANCIA
MR2 SALLY PAREDES NOGUNI
HNERM ONCOLOGIA MEDICA

An Update on Breast Cancer

clinicaloptions.com/oncology

An Update on Breast Cancer

clinicaloptions.com/oncology

QUIMIOTERAPIA ADYUVANTE CON

TRASTUZUMAB
Quimioterapia con trastuzumab por 1 ao es el actual estndar

en el tratamiento adyuvante en cncer de mama HER-2 positivo.

El inicio temprano del tratamiento es crucial: est demostrado

que retraso en el inicio por mas de 6 meses se asoci a mas alto

riesgo de recada y peor OS. Es por eso que se privilegia su
administracin concurrente con la qt no antraciclinica que en
administracin secuencial. *
Pese a ellos se estima que un cuarto de los pacientes habr

recaido a los 10 aos y los sobrevivientes experimentaran

consecuencias asociadas al tratamiento (leucemias, falla
cardiaca). **
* Gallagher CM, More K, Kamath T, et al. Delay initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free
survival in patients with HER2-positive nonmetastatic breast cancer. Breast Cancer Res Treat. 2016;157(1):14556.
** Jackisch C, Piccart MJ, Gelber RD, et al. HERA trial: 10 years follow up of trastuzumab after adjuvant chemotherapy in HER2
positive early breast cancer Final analysis. San Antonio Breast Cancer Sympoisum 2015; abstract PD5-01.

An Update on Breast Cancer

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An Update on Breast Cancer

clinicaloptions.com/oncology

8-YR HERA: 1 VS 2 YRS TRASTUZUMAB

AFTER ADJUVANT CHEMOTHERAPY IN
HER2+ EBC
Patients enrolled in trial from 2001-2005

Current landmark efficacy analysis includes all patients randomly assigned to

trastuzumab who had no evidence of disease for 366 days from randomization

n = 1552 for 1-yr arm

n = 1553 for 2-yr arm

Efficacy endpoints

Primary: DFS

Secondary: OS and time to distant recurrence

Cardiac endpoints

Primary: New York Heart Association class III or IV, confirmed by cardiologist, and LVEF < 50% and
10% below baseline or cardiac death

Secondary: LVEF < 50% and 10% below baseline with confirmation by repeat assessment;
patients with primary cardiac endpoint excluded

Results represent final planned analysis

734 DFS events reported at median follow-up of 8 yrs

725 DFS events originally required to provide 80% power to detect HR: 0.80

Goldhirsch A, et al. SABCS 2012. Abstract S5-2.

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8-YR HERA: 1 VS 2 YRS TRASTUZUMAB

AFTER ADJUVANT CHEMOTHERAPY
Trastuzumab established as standard of care following adjuvant

chemotherapy in HER2-positive early breast cancer based on results

of large randomized trials

HERA previously showed that trastuzumab for 1 yr significantly

extends DFS and OS compared with no trastuzumab in HER2-positive

early breast cancer[1]

Secondary objective of HERA: to evaluate whether 2 yrs of

trastuzumab superior to 1 yr of trastuzumab

Current study[2] reports landmark efficacy analysis of 2 yrs vs 1 yr of

trastuzumab following adjuvant chemotherapy in patients with HER2positive early breast cancer after median follow-up of 8 yrs

Updated efficacy analyses of 1-yr trastuzumab vs observation at

median follow-up of 8 yrs also presented

1. Gianni L, et al. Lancet Oncol. 2011;12:236-244. 2. Goldhirsch A, et al. SABCS 2012. Abstract S52.

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8-YR HERA RESULTS, 1 YR VS 2 YRS OF

TRASTUZUMAB: DFS
DFS, %

Trastuzumab for
1 Yr
(n = 1552)

Trastuzumab for 2
Yrs
(n = 1553)

HR
(95% CI)

P
Value

0.99
.86
(0.85All patients

1.14)
3 yrs

86.7
89.1
5 yrs

81.0
81.6
8 yrs

76.0
75.8
1.05
.67
Hormone receptor
(0.85

positive patients*
1.29)
3 yrs

89.6
90.3
5 yrs

82.9
83.1
8 yrs

77.2
76.1
0.93
.51
Hormone receptor
(0.76

negative patients
1.14)
*92.6% received endocrine therapy. 2.8% received endocrine therapy.
3 yrs

83.8
87.8
5
No
difference
in
OS
between
1-yr
and
2-yr
trastuzumab
arms
through
8
yrs
of

yrs
78.9
80.1
median
follow-up
8

yrs
74.7
75.4
Goldhirsch A, et al. SABCS 2012. Abstract S5-2.

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8-YR HERA RESULTS: SURVIVAL

Trastuzumab for 1
Yr
(n = 1552)

Trastuzumab for 2
Yrs
(n = 1553)

HR (95% CI)

P Value

1.05 (0.86-1.28)

.63

3 yrs

96.5

97.4

5 yrs

91.4

92.6

8 yrs

87.6

86.4

OS, %
All patients

Benefits of 1-yr trastuzumab (52.1% of patients crossed over

to receive trastuzumab beginning in 2005) vs observation

proved durable through 8 yrs of median follow-up, with
benefits seen in both hormone receptorpositive and
hormone receptornegative subpopulations

Goldhirsch A, et al. SABCS 2012. Abstract S5-2.

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8-YR HERA RESULTS: CARDIAC EVENTS

Rates of grade 3/4 adverse events higher in trastuzumab arms

compared with observation arm

Rates of primary cardiac events comparable between 1-yr and 2-

yr trastuzumab arms (0.8 and 1.0%, respectively), but rate of

secondary cardiac events higher with 2 yrs vs 1 yr of
trastuzumab (7.2% vs 4.1%, respectively)
Majority of cardiac events occurring during trastuzumab therapy

reversible upon discontinuation

Goldhirsch A, et al. SABCS 2012. Abstract S5-2.

An Update on Breast Cancer

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TRIAL: 9WK VS 12 MOS OF ADJUVANT

TRASTUZUMAB IN HER2+ EBC
479 females enrolled between February
2007 and December 2010
Stratified by ER status (positive vs
negative)

Patients with HER2positive invasive early

breast cancer who were
operated, who did not
have received
neoadjuvant QT, not (+)
surgical margin, not
bilaterally BC
(N = 497)

Loading dose of 4 mg/kg

followed by 2 mg/kg for every
week or with a loading dose
of 8 mg/kg followed by 6
mg/kg for every three weeks

Trastuzumab for 12 Mos

(trastuzumab continued for 10 more mos)
(n = 298)

Trastuzumab for 9 weeks (trastuzumab stopped)

(n = 181)

J Cancer Res Clin Oncol (2012) 138:21452151

An Update on Breast Cancer

clinicaloptions.com/oncology

TRIAL: 9WK VS 12 MOS OF ADJUVANT

TRASTUZUMAB IN HER2+ EBC
RESULTS, %
DFS 36 months
OS 36 months

J Cancer Res Clin Oncol (2012) 138:21452151.

Trastuzumab for
12 Mos
(n = 298)
85
97

Trastuzumab for
9 wks
(n = 181)
90
96

P
0.132
0.779

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TRIAL: 9WK VS 12 MOS OF ADJUVANT

TRASTUZUMAB IN HER2+ EBC
Trastuzumab related death was not observed.

Asymptomatic and symptomatic ejection fraction

declining in the 9-week trastuzumab treatment occurred
in 1 (0.6 %) patient.
In the 52-week trastuzumab treatment group, 8 (2.6 %)

asymptomatic ejection fraction declining and 4 (1.3 %)

symptomatic ejection fraction declining were observed.
There was one grade 3 allergic reaction in 9-week and one
in 52-week trastuzumab treatment groups.

J Cancer Res Clin Oncol (2012) 138:21452151

An Update on Breast Cancer

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SENDUR ET AL. TURKEY. 9WK VS 12 MOS

OF ADJUVANT TRASTUZUMAB IN HER2+
EBC

An Update on Breast Cancer

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SENDUR ET AL. TURKEY. 9WK VS 12 MOS

OF ADJUVANT TRASTUZUMAB IN HER2+
EBC

An Update on Breast Cancer

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SENDUR ET AL. TURKEY. 9WK VS 12 MOS

OF ADJUVANT TRASTUZUMAB IN HER2+
EBC (AE)

Cardiotoxicity was observed to be significantly higher in the 52

week trastuzumab arm (15.5%) compared to the 9 week

trastuzumab arm (1.9%),

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PHARE: 6 VS 12 MOS OF ADJUVANT

TRASTUZUMAB IN HER2+ EBC
Stratified by ER status (positive vs
negative), chemotherapy + trastuzumab
timing (concurrent vs sequential)

Patients with HER2positive invasive early

breast cancer who
underwent at least
4 cycles of (neo)adjuvant
chemotherapy +
trastuzumab initiation in
the previous 12 mos
(N = 3384)

Trastuzumab for 12 Mos

(trastuzumab continued for 6 more mos)
(n = 1690)

Trastuzumab for 6 Mos

(trastuzumab stopped)
(n = 1690)

Left ventricular ejection fraction values every 3 mos; mammography every 6 mos up to 60 mos
Pivot X, et al. SABCS 2012. Abstract S5-3.

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PHARE: DFS AFTER 6 VS 12 MOS OF

ADJUVANT TRASTUZUMAB IN HER2+ EBC
DFS Events, %
Overall
Local recurrence
Regional recurrence
Distant recurrence
Contralateral breast cancer
Second primary malignancy
Death

Trastuzumab for 12
Mos
(n = 1690)
10.4
1.1
0.6
6.4
0.4
1.5
0.4

Trastuzumab for 6 Mos

(n = 1690)
13.0
1.4
0.5
8.3
0.7
1.5
0.5

DFS HR for 12 vs 6 mos of trastuzumab was 1.28 (95% CI: 1.05-1.56; P = .29),
Trastuzumab
for 12 margin
Trastuzumab
for 6
with 95% CI that included prespecified
noninferiority
of 1.15, making
Mos
Mos
DFS,
probability,
%
results
inconclusive
regarding noninferiority
(n = 1690)
(n = 1690)
1 yr
97.0
95.5
2 yrs
93.8
91.2
3 yrs
90.7
87.8
4 yrs
87.8
84.9
Pivot X, et al. SABCS 2012. Abstract S5-3. Reproduced with permission.

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PHARE TRIAL: PREDETERMINED DFS

SUBSET ANALYSIS
DFS benefit with 12 mos of trastuzumab in ER-negative patients who

received sequential adjuvant therapy

Subgroup

Patients, n

ER negative, sequential
therapy

626

ER positive, sequential
therapy

850

ER negative, concurrent
therapy

786

ER positive, concurrent
therapy

1118

Pivot X, et al. SABCS 2012. Abstract S5-3.

DFS HR for 12 vs 6 Mos

of Trastuzumab (95%
CI)
1.57 (1.08-2.28)
1.25 (0.81-1.91)
1.10 (0.73-1.65)
1.23 (0.83-1.82)

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PHARE TRIAL: PREDETERMINED DFS

SUBSET ANALYSIS

very low risk (no adverse factor, score = 0): node negative and tumour size 2 cm; low risk
(one adverse factor, score = 1): 13 positive nodes and tumour size 2 cm, or node negative
and tumour size >2 cm; intermediate risk (score = 2): 13 positive nodes and tumour size >2
cm, or >3 positive nodes and tumour size 2 cm; high risk (score = 3): >3 positive nodes and
tumor size >2 cm.

An Update on Breast Cancer

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