HER 2+ Breast Cancer

Breast cancer is the most common cancer in women in the world

Globocan, 2012
 BREAST CANCER
Breast Cancer is a systemic disease
Treatment failure and mortality were
mostly caused by uncontrolled distant
metastasis
1 cm3 of tumor burden, 10 20% probably
more had had distant metastasis
When metastasis started? unknown
Metastasis was genetically defined (not
mechanically defined) could happen
any time of tumor growth
J Intern Med 2013 Aug;274(2):113-26
 Sub types in Breast Cancer
Intrinsic Clinico-pathologic surrogate definition Notes
subtype
Luminal A Luminal A-like The cut-point between high and low values for Ki-67 varies between
all of: laboratories.a A level of <14% best correlated with the gene-expression
ER and PgR positive definition of Luminal A based on the results in a single reference
HER2 negative laboratory [23]. Similarly, the added value of PgR in distinguishing
Ki-67 lowa between Luminal A-like and Luminal B-like subtypes derives from the
Recurrence risk low based on work of Prat et al. which used a PgR cut-point of 20% to best
multi-gene-expression assay (if correspond to Luminal A subtype [24]. Quality assurance programmes
available)b are essential for laboratories reporting these results.
Luminal B Luminal B-like (HER2 negative) Luminal B-like disease comprises those luminal cases which lack the
ER positive characteristics noted above for Luminal A-like disease. Thus, either a
HER2 negative high Ki-67a value or a low PgR value (see above) may be used to
and at least one of: distinguish between Luminal A-like and Luminal B-like (HER2
Ki-67 high negative).
PgR negative or low
Recurrence risk high based on
multi-gene-expression assay (if
available)b

Luminal B-like (HER2 positive)

ER positive
HER2 over-expressed or amplified
Any Ki-67
Any PgR
Erb-B2 HER2 positive (non-luminal)
overexpression HER2 over-expressed or amplified
ER and PgR absent
Basal-like Triple negative (ductal) There is an 80% overlap between triple-negative and intrinsic basal-like
ER and PgR absent subtype. Some cases with low-positive ER staining may cluster with
HER2 negative nonluminal
subtypes on gene-expression analysis. Triple negative also
Sthistological
includes some special Gallen Guideline, 2013
types such as adenoid cystic
 Breast Cancer and Early Detection
Early diagnosis means a better chance of
successful treatment
Mammography is the best tool doctors have to
screen for breast cancer and can detect
cancers too small to be felt
Recommendations differ; many state that
women obtain a mammogram each year,
starting at the age of 40
Women are encouraged to discuss screening
with their doctors
SADARI (PemerikSAan payuDAra sendiRI )
 SADARI

BSE is recommended to be done between 7 days to 10

days after the first day of menstruation. At this time,
breast density is reduced.
If you no longer menstruate, do BSE on a fixed date
every month, for example the first day of each month.
BSE is not supposed to replace physical breast
examination schedule by doctors and schedule
mammography.
Women 20 years and older

American Cancer Society, 2014

 MAMMOGRAM

Its recommended for women aged >40 years

Avoid making mammogram during the week before menstruation. The
breasts will be less tender and swollen
American Cancer Society, 2014
 Breast Ultrasound
Painless, no radiation
Less expensive than other options, such as MRI
Ultrasound helps distinguish between cysts and solid
masses
It can be used to look for enlarged lymph nodes.
Breast ultrasound is often used to guide a needle to
biopsy breast lesions and enlarged lymph nodes
The use of ultrasound instead of mammograms for
breast cancer screening is not recommended

American Cancer Society, 2014

WHAT IS HER2?
 erbB2 gene encodes HER2
HER2 is encoded by the erbB2 gene, which maps to
chromosome Hs17q21

Normal cells have two copies of the erbB2 gene

Approved names
v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2
Neuro/glioblastoma derived oncogene homolog (avian)

erbB2 encodes one of a four member family of EGFRs

HER1, c-erbB-1, EGFR
HER2, c-erbB-2, HER-2/neu
HER3, c-erbB-3
HER4, c-erbB-4

Park JW, et al. Clin Breast Cancer 2008;8:392401.

 Overview of HER2
HER2 is a membrane-bound cell
surface RTK1
Overexpression of HER2 in breast
Extracellular cancer occurs in ~1820% of
region cases1, and is associated with:
Transmembrane Cell growth, proliferation,
region survival/decreased apoptosis, cellular
migration, and angiogenesis2,3
Cell membrane Poorer prognosis, such as shorter time to
relapse as well as a shorter overall survival4
Treatment with HER2-targeted
agents improves outcomes for
Intracellular
region with patients with HER2-positive disease5
tyrosine kinase High-quality HER2 testing is essential to
activity ensure optimal identification of patients
with HER2-positive tumours eligible for
C-terminal tail with HER2-targeted therapy
phosphorylation sites

RTK, receptor tyrosine kinase

1. Wolff et al 2007; 2. Sliwkowski et al 2004; 3. Prenzel et al 2001;
4. Slamon et al 1989; 5. Dawood et al 2010
 HER2 gene amplification induces protein
overexpression
Gene amplification is the cellular process characterised by production
of multiple copies of a particular gene or genes to amplify the
phenotype that the gene confers on the cell
Amplification and/or overexpression of HER2 has been reported in
numerous cancers including breast, gastric, colon, bladder, ovarian,
endometrial, lung, uterine cervix, head and neck, pancreatic, biliary
and oesophageal carcinomas1,2

Normal HER2 expression HER2 overexpression

1. Koeppen HK, et al. Histopathology 2001;38:96104;
 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 is the preferred dimerization
partner in cancer

Role of HER2 gene expression in breast carcinoma. Mnard 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.

Although all 4 HER family receptors are capable of

dimerizing with each other, HER2 is the preferred
dimerization partner1
Reference: 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.
 Clinical significance of HER2
status
Understanding the biology of breast cancer is
now of paramount importance

Conventional tumour Biomarkers (such as HER2)

classification Provide prognostic and
TNM staging system predictive value
Histological grade Intrinsic subtype
Lymph node status Other genomic signatures

Assessment of HER2 status is essential to

determine patient eligibility for HER2 targeted
therapy
Carlson RW, et al. JNCCN 2006:4(Suppl 3):S1S22. 2. Bang YJ, et al. Lancet 2010; 376:687 697.
 Identifying the right patient:
HER2 testing
High-quality HER2 testing is essential to
ensure optimal identification of patients with
HER2-positive tumours eligible for HER2-
targeted therapy
There are several HER2 testing methods
currently used to detect HER2 protein or
gene amplification
IHC, FISH, CISH, SISH, dual SISH
HER2 testing is required for breast cancer
patients to determine the right treatment
Penault-Llorca F, et al. The Breast 2013; 22:200202;
Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).
 ASCO/CAP guidelines*:
Updates to the definitions and criteria for HER2-
positivity
Definition of IHC 3+ changed from uniform intense membrane
staining of >30% of invasive tumour cells to complete and intense
circumferential membrane staining within >10% of tumour cells

In ISH testing, a positive result is defined as

A HER2/CEP17 ratio of 2.0, reduced from 2.2
A HER2/CEP17 ratio of <2.0 with a HER2 copy number 6
A HER2 copy number 6 in a single-probe test (reduced from >6 copies)

Recommended that reflex tests are carried out to confirm equivocal

test results
Use of an FDA-approved IHC, bright-field ISH or FISH assay
is preferred

* Please note: International guidelines may not be in line with current national guidelines.
ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists.
Wolff AC, et al. J Clin Oncol 2013 (Epub ahead of print).
 Breast cancer HER2 testing
algorithm
Patient tumour sample

IHC ISH
(FISH or CISH)

0 1+ 2+ 3+

+
Retest with ISH Eligible for
(FISH, CISH, HER2-targeted
SISH) therapy Eligible for
HER2-targeted
therapy
+

Eligible for
HER2-targeted
therapy

If primary ISH testing is used, patients whose tumours overexpress the HER2 protein (i.e. IHC 3+) may not always be identified.
Hanna W & Kwok K. Mod Pathol 2006; 19:481487.
 Breast Cancer Treatment
Depends on the staging and type of the disease
Mutimodal
Surgery
Systemic therapy
Hormonal therapy
Chemotherapy
Targeted Therapy
Radiotherapy

NCCN Guidelines v.1. 2015

 Chemoterapy for
metastatic breast cancer

Combinations
Single Agent/ Chemoterapy
with targeted
monotherapy combinations
therapy

Doxorubicin
Paclitaxel FAC Bevacizumab +
Capecitabine FEC Paclitaxel
(until disease AC Trastuzumab +
progression) EC docetaxel
Gemcitabine CMF Lapatinib +
Vinorelbine Docetaxel/capecitabine capecitabine
Eribuline

mAB for mBC used until disease progression

NCCN Guidelines 2015
Xeloda prescribing information
Herceptin prescribing Informatio
Avastin prescribing information
ANTI HER2 THERAPY
 Targeting erbB/HER family
Cetuximab Trastuzumab Monoclonal
Panitumumab Pertuzumab antibodies

Extracellular

Membrane

Intracellular
K K K

EGFR HER2 HER3 HER4

Gefitinib
Lapatinib
Erlotinib
Tyrosine kinase
EKB-569
inhibitors
 Lapatinib
Classification : tyrosine kinase inhibitor
Mechanism of action Receptor tyrosine
kinase inhibitor at ErbB-1 and ErbB-2
Route of administration Oral

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer, 2007
 Trastuzumab
anti-HER2 therapy for breast cancer

A humanized monoclonal antibody

Bound the extracelullar domain of
HER2
Various mechanisms of action
Trastuzumab : Mechanism of Action

Activation of Prevention of formation of

ADCC p95HER2

Inhibition of cell
proliferation Inhibition of
HER2-regulated angiogenesis
THE EVIDENCE FOR ANTI-
HER2 THERAPY IN BREAST
CANCER
 Treatment guidelines for
HER2-positive EBC
1 year of trastuzumab is recommended
across international guidelines
Adjuvant
therapy Recommended patient groups Administration
HER2-positive tumours 1 cm Preferred: concurrent use of trastuzumab with
chemotherapy
HER2-positive node-negative tumours 0.51.0
1 year of
St. Gallen1 cm (pT1b) Acceptable: chemotherapy followed by
trastuzumab trastuzumab sequentially
Excludes: HER2-positive node-negative tumours
0.10.5 cm (pT1a)
HER2-positive tumours 1 cm Trastuzumab may be started in parallel with a
taxane
1 year of Use of trastuzumab should be discussed with
ESMO2 patients with small node-negative HER2-positive Trastuzumab should not be given concurrently
trastuzumab
breast cancers with an anthracycline outside the context of a
clinical trial
Category 1 recommendation: patients with Preferred: doxorubicin and cyclophosphamide
HER2-positive tumours >1 cm followed by concurrent administration of
trastuzumab with taxane pertuzumab
Category 2 recommendation: patients with HER2-
1 year of positive node-negative tumours Preferred: docetaxel, carboplatin and
NCCN3
trastuzumab 0.61.0 cm trastuzumab. pertuzumab. For other
regimens refer to NCCN guidelines
HER2-positive node-negative pT1a or pT1b
tumours: use of trastuzumab to be based on Acceptable: chemotherapy followed by
individual benefit:risk docetaxel +trastuzumab pertuzumab

1. Goldhirsch A, et al. Ann Oncol 2013; 24:22062223;

2. Senkus E, et al. Ann Oncol 2013; 24(Suppl 6):vi7vi23;
3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) : Breast Cancer. Version 1. 2015
 Pivotal studies Trastuzumab
in HER2-positive EBC
Extensive clinical programme involving >12,000 patients
Follow-
Study N Treatment arms up
(yrs)

CT* RT observation
HERA1 5102 CT* RT Herceptin (trastuzumab) 1 year 4
CT* RT Herceptin (trastuzumab) 2 years

AC docetaxel
BCIRG AC docetaxel+Herceptin (trastuzumab) Herceptin (trastuzumab)
3222 5
0062 Docetaxel+carboplatin+Herceptin (trastuzumab) Herceptin
(trastuzumab)

AC paclitaxel
NCCTG
3505 AC paclitaxel Herceptin (trastuzumab) 4
N98313
AC paclitaxel+Herceptin (trastuzumab) Herceptin (trastuzumab)

NSABP AC paclitaxel
2101 4
B-313 AC paclitaxel+Herceptin (trastuzumab) Herceptin (trastuzumab)

CT, chemotherapy (*selected from a list of approved regimens consisting of 4 cycles);

RT, radiotherapy
1. Gianni et al 2011; 2. Slamon et al 2011; 3. Perez et al 2011
 DFS and OS benefits demonstrated during long-term
follow-up in the four pivotal clinical trials of
trastuzumab for 1 year

DFS OS
Follow-up
Study (years) N HR p value HR p value
1 3387 0.54 < 0.0001 0.76 0.26
HERA14 2 3401 0.64 < 0.0001 0.66 0.0115
CTRTT vs. CTRT 4 3401 0.76 < 0.0001 0.85 0.1087
8 3399 0.76 < 0.0001 0.76 0.0005
2 3351 0.48 < 0.0001
NCCTG N9831/
NSABP B-3157 4 4045 0.52 < 0.001 0.61 < 0.001
ACTax+TT vs. ACTax
8.4 4046 0.60 < 0.0001 0.63 < 0.0001
BCIRG 0068
ACTax + T vs. ACTax 0.64 < 0.001 0.63 < 0.001
5.4 3222
Tax+CbT vs. ACTax 0.75 0.04 0.77 0.04

AC, doxorubicin and cyclophosphamide; Cb, carboplatin; CT, chemotherapy; DFS, disease-free survival;
HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, trastuzumab; Tax, taxane.
1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672; 2. Smith I, et al. Lancet 2007; 369:2936;
3. Gianni L, et al. Lancet Oncol 2011; 12:236244; 4. Goldhirsch A, et al. Lancet 2013; 382:10211028;
5. Romond EH, et al. N Engl J Med 2005; 353:16731684; 6. Perez EA, et al. J Clin Oncol 2011; 29:33663373;
7. Romond EH, et al. SABCS 2012. Oral presentation S5-5; 8. Slamon D, et al. N Engl J Med 2011; 365:12731283.
 H0648g and M77001: addition of trastuzumab to
chemotherapy as first-line therapy increases OS
Addition of trastuzumab to chemotherapy as a first-line therapy
for HER2-positive mBC significantly increases OS : extends life
H0648g1 M770012
Trastuzumab + chemotherapy (n=235) Trastuzumab + docetaxel (n=92)
100 Chemotherapy (n=234) 1.0 Docetaxel (n=94)

Survival probability
Survival probability

80 0.8
RR=0.80 (95% CI=0.64,1.00)
p=0.046 p=0.0325
60 0.6

40 0.4

20 0.2
20.3 25.1 22.7 31.2
0 0
0 5 15 25 35 45 0 5 10 15 20 25 30 35 40 45 50
Time (months) Time (months)
TTP :11,7 mo (16 cycles)

OS, overall survival; RR, relative risk of death.

1. Slamon DJ, et al. N Engl J Med 2001; 344:783792;
2. Marty M, et al. J Clin Oncol 2005; 23:42654274. .
 Safety profile of anti-HER2
agents
HER2 positive breast cancer
Trastuzumab
Generally well tolerated with a predictable safety profile13
There was little difference in the number and severity of adverse events observed for
patients treated with chemotherapy alone or in combination with trastuzumab3
Most common adverse event profile typically includes pain, asthenia, fever, diarrhoea
and nausea/vomiting13
Lapatinib
A generally well tolerated treatment4,5
Adverse event profile typically includes rash, diarrhoea, nausea/vomiting, stomatitis,
fatigue and anorexia4,5

HER2 positive advanced gastric cancer

Addition of trastuzumab to chemotherapy did not impact overall or cardiac safety profile7
Most common adverse events were nausea, neutropenia, vomiting and anorexia7

1. Piccart-Gebhart M et al. N Engl J Med 2005;353: 16591672;

2. 2. Marty M et al. J Clin Oncol 2005; 23:42654274;
3. 3. Slamon D et al. 2001;344:783-792;
4. 4. Cameron D et al. Breast Cancer Res Treat 2008;112:533543;
5. 5. Oakman C et al. Cancer Manag Res 2010; 2:1325; 6.Bang YJ et al. Lancet 2010;376:687697.
 Take Home Message
Early detection is crucial for survival
All primary breast cancer specimens and metastases
should have HER2 test performed
Status of HER-2 in Breast Cancer Patients will define
the treatment for patients
There are many options for breast cancer available now
Anti HER2 treatment : Trastuzumab, Pertuzumab,
Lapatinib
Trastuzumab is a standard treatment for HER2+ Breast
Cancer, 18 cycles for eBC (1 year), till disease
progression for mBC