Treatment of her2 positive breast cancer
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Transcript of Treatment of her2 positive breast cancer
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
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