This document discusses treatment of HER2 positive breast cancer. It describes HER2 as a tyrosine kinase receptor that is overexpressed in 15-30% of breast cancers and promotes cell proliferation. Testing methods like IHC and FISH are used to detect HER2 status. Targeted therapies have been developed that block HER2 signaling including Trastuzumab, Pertuzumab, Lapatinib, and T-DM1. Several neoadjuvant and adjuvant clinical trials are summarized that demonstrate improved outcomes when these anti-HER2 therapies are added to chemotherapy regimens for both early-stage and metastatic HER2 positive breast cancer.

1. Treatment of HER2 Positive
Breast Cancer
Dr. Manar Almusarhed
24 Mar 2016
Milton Keynes University Hospital

2. Human Epidermal growth factor Receptor 2
• One of the Tyrosine Kinase Receptors
(HER1,HER2,HER3,HER4)
• Function : Heterodimerization with
other family members such as HER1
and HER3 initiates a variety of signaling
pathways leading to Cell proliferation,
survival, differentiation, angiogenesis,
and invasion.

3. Overexpression
• HER2 is overexpressed in 15–30%of
invasive breast cancer.
• Associated with high-grade disease,
nodal metastases and tumour size.
• HER2 Overexpression occurs also in
other forms of cancers also such as
stomach, ovary, uterine serous
endometrial carcinoma, colon,
bladder, lung, uterine cervix, head and
neck, and esophagus.

4. Testing for HER2
• Immunohistochemistry IHC
• Fluorescence In Situ
Hybridization (FISH).

5. Targeting HER2
A. Trastuzumab: Blocks domain IV
HER2 (1998)
B. Pertuzumab: Blocks domain II
HER2 (2007)
C. Lapatinib : Blocks Intracellular ATP
pocket of HER1 & HER2 (2012)
D. Ado-Trastuzumab emsantine
(T-DM1) : monoclonal Ab –
Cytotoxic drug (2013)

6. Neoadjuvant trials

7. Buzdar et al., 2005
• Forty-two patients with HER2-positive
disease randomly assigned to either
four cycles of paclitaxel followed by
four cycles of FEC or to the same
chemotherapy with simultaneous
weekly trastuzumab for 24 weeks
• Results: pCR rates were 26% and 66 %
for chemotherapy (n = 16) and
trastuzumab plus chemotherapy (n =
18), respectively (P = .02)
• Conclusion: Adding trastuzumab to
chemotherapy significantly increased
pCR.

8. NOAH trial : Phase III
• 235 patients with HER2-positive disease were
enroled, of whom 118 received
chemotherapy alone and 117 received
chemotherapy plus trastuzumab.
• Results: pCR rates were 43% and
22% for chemotherapy and Trustuzumanb
plus chemotherapy respectively.
• Conclusion: Adding trastuzumab to
chemotherapy significantly increased pCR.

9. NeoSphere (Gianni et al., 2012)

10. NeoALTTO Trial

11. UK EPHOS-B trial (2016)
• Multicentre, 2-part randomised trial in
patients with operable newly diagnosed
HER2+ primary BC
• EPHOS-B was designed to measure the effect
of 10–12 days' pre-operative anti-HER2
therapy on proliferation and apoptosis in
HER2+ BC patients
• Trial started with part1 then amended to part
2
• Conclusion : The early reduction or absence
of invasive disease in approximately quarter
of patients after only 11 days' preoperative
combination HER2 therapy identifies cancers
addicted to the HER2 pathway.
MDR: Minimal Residual Disease < 5mm
IQR: interquartile range

12. Adjuvant trials

13. HERA trial
• Randomised three-arm
multicente comparison of 1 year
and 2 years of Trustuzumab Vs
no Trustuzumab in women who
have completed chemotherapy.

14. HERA trial
• Findings:
• Conclusion: Two years of adjuvant
Trastuzumab is not more effective
than is 1 year of treatment .
One year of treatment provides a
significant disease-free and overall
survival benefit compared with
observation.
Endpoint One year
Herceptin vs.
observation*
One year vs.
two years
Herceptin**
Disease-free
survival
•HR=0.76,
p<0.0001
•24% reduction
in the risk of
disease
recurrence
•HR=0.99,
p=0.86
•No difference
Overall survival •HR=0.76,
p=0.0005
•24% reduction
in the risk of
death
•HR=1.05,
p=0.63
•No difference

15. BCIRG 006 trial
• 3222 women with HER2-positive early-stage
breast cancer enroled in this trial.

16. BCIRG 006 trial
• Findings: The estimated disease-free
survival rates at 5 years were 75%
among patients receiving AC-T, 84%
among those receiving AC-T plus
trastuzumab, and 81% among those
receiving TCH.

17. BCIRG 006 trial
• Overall survival:
• Conclusion: Addition of 1 year
of adjuvant Trastuzumab
significantly improved disease-
free and overall survival among
women with HER2-positive
breast cancer.

18. NCCTG N9831 and NSABP B-31
• 4,046 patients with HER2-positive
operable breast cancer were enrolled
to receive doxorubicin and
cyclophosphamide followed by
paclitaxel with or without
Trastuzumab in both trials.

19. NCCTG N9831 and NSABP B-31

20. NCCTG N9831 and NSABP B-31

21. NCCTG N9831 and NSABP B-31
• Results: Median time on study was 8.4 years.
Adding trastuzumab to chemotherapy led to a
37% relative improvement in OS (hazard ratio
[HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and
an increase in 10-year OS rate from 75.2% to
84%. These results were accompanied by an
improvement in DFS of 40% (HR, 0.60; 95% CI,
0.53 to 0.68; P < .001) and increase in 10-year
DFS rate from 62.2% to 73.7.
• Conclusion: Addition of trastuzumab to
paclitaxel after doxorubicin and
cyclophosphamide in early-stage HER2-
positive breast cancer results in a substantial
and durable improvement in survival as a
result of a sustained marked reduction in
cancer recurrence.

22. Metastatic disease trials
• Salmon et al (2001)
• Marty et al (2005)
• CONCLUSIONS:Trastuzumab increases
the clinical benefit of first-line
chemotherapy in metastatic breast
cancer that overexpresses HER2.

23. CLEOPATRA trial
• randomized, double-blind,
placebo-controlled, phase III
trial
• 808 Patients were enrolled in
this trials

24. CLEOPATRA trial
• Conclusion: significant
improvement in overall survival
with pertuzumab, trastuzumab,
and docetaxel in patients with
HER2-positive metastatic breast
cancer, compared with placebo,
trastuzumab, and docetaxel

25. EMILIA trial
• multi-center, international
randomized study of T-DM1 vs.
capecitabine and lapatinib, for
trastuzumab refractory HER2+
metastatic breast cancer.

26. EMILIA trial

27. EMILIA trial
• Conclusion: T-DM1 significantly
prolonged progression-free and
overall survival with less toxicity
than Lapatinib plus Capecitabine
in patients with HER2-positive
advanced breast cancer
previously treated with
Trastuzumab and a Taxane

28. Ongoing Trials in Metastatic disease

29. Phase III MIRRIANNE trial

30. NCCN guideline in HER2 +ve metastatic
disease

31. NCCN guideline in HER2 +ve
Neoadjuvant/adjuvant settings