This document discusses targeted therapies for breast cancer that express human epidermal growth factor receptor 2 (HER2). It describes several approved HER2-targeted agents including trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), and lapatinib. It also discusses everolimus and palbociclib which target other pathways important in breast cancer. Trastuzumab was the first approved HER2-targeted monoclonal antibody and works by inhibiting HER2 signaling. Pertuzumab inhibits HER2 dimerization and is used with trastuzumab. T-DM1 delivers the chemoagent emtansine directly to HER2-positive cells. Ever

1. Targeted Therapy in Breast
Dr Nagarjuna B
Senior Resident
Dept Of Radiation Oncology

2. Flow of Presentation
• Human Epidermal growth factor Receptor
• Trastuzumab
• Pertuzumab
• Ado-trastuzumab emtansine (T-DM1)
• Lapatinib
• Everolimus
• Palbocilib

3. • HER2 gene is amplified in about 15–30% of breast
cancers defined as 3+ immunohistochemistry or
fluorescence in situ hybridization amplification ratio
≥2.0.
• HER2+ breast cancers tend to be more aggressive
than other types of breast cancer with a higher
chance of metastasis and poor clinical outcomes.
• The HER family consists of four main receptors ‐
HER1, HER2, HER3, and HER4

4. 4:31:33 PM
TK TKTK
erbB1
HER1
EGFR
erbB2
HER2
neu
erbB3
HER3
erbB4
HER4
No specific
ligands -
often acts as
dimer partner Heregulins
NRG2
NRG3
Heregulins
β-cellulin
EGF, TGFa , b Cellulin
Amphiregulin, HB-EGF
Human Epidermal Growth Factor Receptor Family

5. 4:31:33 PM
TK Intracellular
Domain
Transmembrane
Domain
Extracellular
Domain
EGFR Structure

6. 4:31:33 PM
TKTK TKTK
erbB1
HER1
EGFR
erbB2
HER2
neu
erbB3
HER3
erbB4
HER4
EGFR Homo Dimerisation
EGFRStimulation&dimerisation

7. 4:31:33 PM
TK TKTK
erbB1
HER1
EGFR
erbB2
HER2
neu
erbB3
HER3
erbB4
HER4
Hetero Dimerisation
Risk for cancer
EGFRstimulationcont…

8. 4:31:33 PM
TK
EGFR Function in Normal Cell
TKATP ATP
Cell Proliferation Antiapoptosis
Angiogenesis
Gene Transcription
Cell Cycle Progression
+

9. 4:31:33 PM
TKTK
EGFR signal transduction in tumour cells
Survival
(anti-apoptosis)
PI3-K
STAT3
AKTPTEN
MEK
Gene transcription
MAPK
Proliferation/
maturation
Chemotherapy /
radiotherapy
resistance
Angiogenesis
Metastasis
pY
pY
RAS RAF
SOS
GRB2pY
G1
SM
G2

11. • Currently approved Anti HER2 agents are
1. Trastuzumab
2. Pertuzumab
3. T-DM1 or ado-Trastuzumab Emtansine

12. • Trastuzumab is the first humanized monoclonal
antibody which binds with the HER2 (extracellular
domain receptors IV) and reduces tumor cell
proliferation and survival.
• MOA: inhibits tyrosine kinase signalling of receptor
Activates ADCC
G1 arrest by modulating CDKs
Induction of apoptosis

13. Decreased risk of
recurrence 39 – 48%

14. TREATMENT OVERVIEW
.
 Trastuzumab to be administered concomitantly with CT rather than
sequentially.
 Following completion of chemotherapy plus trastuzumab, trastuzumab is used
as a single agent (ie, maintenance treatment) for a total treatment duration of
52 weeks.
 Endocrine therapy concurrently with trastuzumab is recommended only during
maintenance treatment (following completion of adjuvant chemotherapy).

15. Patients with cardiac risk factors
 Potential risk factors associated with the development of trastuzumab-
related cardiotoxicity include :
- previous or concurrent anthracycline use,
- age greater than 50,
- pre-existing cardiac dysfunction,
- high body mass index,
- Treatment with antihypertensive agents.
 For patients with cardiac risk factors who are candidates for adjuvant HER2-
directed treatment, careful monitoring of cardiac function during and after
treatment is necessary.
 Presence of cardiac risk factors alone should not exclude HER2-positive
patients from HER2-targeted therapy

16. Nccn

20. Pertuzumab

21. • The HER2/HER3 heterodimer is considered the most potent
HER dimer pair for ligand‐induced tyrosine phosphorylation,
and downstream signaling.
• Trastuzumab blocks homodimerization but cannot inhibit
heterodimerization, i.e. it inhibits ligand‐ independent HER2
signaling, prevents HER2 activation by extracellular domain
shedding, and flags cells for destruction by the immune
system

22. • However, it cannot prevent ligand‐ activated HER2/HER3 or
HER2/HER1 heterodimerization, a potential escape
mechanism for tumor cells from the inhibitory effects of
trastuzumab.
• In preclinical studies, HER2/HER3 signaling was required for
the proliferation of HER2‐amplified cancer cells, as a
consequence, blockade of ligand‐induced HER2/HER3
heterodimers in combination with inhibition of
ligand‐independent homodimerization of HER2 offers a
promising synergistic therapeutic strategy for HER2+ breast
caner.

23. • Thus, there is a need for a potential agent,
such as Pertuzumab, which can also prevent
heterodimerization, resulting in more potent
growth inhibition.

24. • Pertuzumab targets the extracellular dimerization
domain (subdomain II) (while trastuzumab binds to
domain IV.)
• of the HER2 receptor and blocks ligand‐dependent
heterodimerization of HER2 with other HER
members (HER1, HER3, and HER4) and
homodimerization with other HER2 receptors

31. NCCN

33. Ado-trastuzumab emtansine (T-DM1)

37. nccn

38. Lapatinib

44. Pre operative Herceptin
• Gepar Quinto trial- EC(4) D + Trastuzumab pCR – 30.3%
D + Lapatinib pCR – 22.7%
• Neo ALTTO trial- Lapatinib + Pacli pCR – 24%
Trastuzumab + Pacli pCR – 29%
T + L + Pacli pCR – 51.3%
• NeoSphere trial – Pertuzumab + Trastuzumab + paclitaxel
pCR – 45.8%
• Tryphaena trial – Pertuzumab + trastuzumab + Doce + Carbo
(in early & LABC) pCR – 66.2%

45. Everolimus

46. • In hormone receptor positive breast cancer
cells, endocrine resistance develops as a result
of aberrant signaling through the
phosphatidylinositol 3-kinase (PI3K)-Akt-
mTOR pathway.

47. • BOLERO-2 was an international, double-blind,
phase 3 study in which patients were
randomised in a 2:1 ratio between oral
everolimus and matching placebo (at a dose of
10 mg daily). All patients received exemestane
in the dose of 25 mg daily.

51. • Response rates and clinical benefit rates (patients
with complete response, partial response, or stable
disease for greater than six months) were higher in
the combination arms (12.0% vs. 1.3% and 50.5% vs.
25.5%; P<0.0001), respectively.
• Patients with only bone metastases benefited from
the combination.

52. • These results are similar to the benefit seen with
chemotherapy (without their toxicity). For instance,
the median PFS with capecitabine, taxanes or
anthracyclines also ranges between 6.2 months and
8.2 months.

57. Palbocilib
• Several cell-cycle checkpoint proteins control
progression through cell division from G1/S through
M-phase including cyclin-dependent kinase (CDK).
Among these proteins, those targeted against the
cyclin-dependent kinases, (i.e., CDK inhibitors) are
the most advanced therapeutics for breast cancer.

58. • CDK 4/6 and cyclin D regulate the G1/S transition
through regulation of the retinoblastoma (RB)
oncoprotein. When RB is phosphorylated,
transcription factors are released allowing the cell to
transition from G1 to S phase.
• Inhibitors of CDK 4/6, therefore, keep RB in the
unphosphorylated state and transcription factors
remain bound to it, ultimately resulting in G1 arrest.

59. • Palbociclib is the first-in-class, oral, reversible, highly
selective inhibitor of CDK4/6 that has been approved
for front-line treatment of metastatic ER+/HER2-
breast cancer in combination with an AI

60. • PALOMA-1 trial demonstrated a statistically
significant improvement in PFS when palbociclib was
added to letrozole in the treatment of
postmenopausal women with metastatic ER+/HER2-
breast cancer who had not previously received any
systemic treatment for their advanced disease.
• With a median follow-up of approximately 30
months for the palbociclib plus letrozole group and
28 months for the letrozole alone group, the median
PFS was 20.2 months (95% CI 13.8–27.5) and 10.2
months (95% CI 5.7–12.6), respectively, (HR 0.488,
95% CI 0.319–0.748; one-sided p = 0.0004).

61. nccn

63. Thank U