Treatment of HER2 Positive Breast Cancer

Dr. Manar Almusarhed

24 Mar 2016

Milton Keynes University Hospital

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.

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.

Testing for HER2• Immunohistochemistry IHC• Fluorescence In Situ

Hybridization (FISH).

Targeting HER2A. 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)

Neoadjuvant trials

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.

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.

NeoSphere (Gianni et al., 2012)

NeoALTTO Trial

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 < 5mmIQR: interquartile range

Adjuvant trials

HERA trial• Randomised three-arm

multicente comparison of 1 year and 2 years of Trustuzumab Vs no Trustuzumab in women who have completed chemotherapy.

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

 BCIRG 006 trial• 3222 women with HER2-positive early-stage

breast cancer enroled in this trial.

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.

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.

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.

NCCTG N9831 and NSABP B-31

NCCTG N9831 and NSABP B-31

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.

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.

CLEOPATRA trial• randomized, double-blind,

placebo-controlled, phase III trial • 808 Patients were enrolled in

this trials

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

EMILIA trial• multi-center, international

randomized study of T-DM1 vs. capecitabine and lapatinib, for trastuzumab refractory HER2+ metastatic breast cancer.

EMILIA trial

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

Ongoing Trials in Metastatic disease

Phase III MIRRIANNE trial

NCCN guideline in HER2 +ve metastatic disease

NCCN guideline in HER2 +ve Neoadjuvant/adjuvant settings

THANK YOU