Cardiotoxicity in Metastatic Her 2 Positive Patients Treated With Trastuzumab ,Pertuzumab and Taxanes

Breast cancer is the leading cancer in women in Israel with 4000 new cases every year.

Approximately 15-25% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive and it has been well known that HER2 overexpression is associated with more aggressive phenotype and poor prognosis with resistance to certain chemotherapeutic agents.

Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity.

Addition of trastuzumab to chemotherapy significantly improved response rate, time to disease progression and reduction of death compared to chemotherapy alone in HER2-positive metastatic breast cancer (MBC). Thus, anti-HER2 treatment is a standard therapeutic approach for HER2-positive MBC patients with visceral crisis. Trastuzumab administration as an adjuvant and in metastatic HER2 positive breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The incidence of trastuzumab-mediated cardiotoxicity were 27% with antracycline combination and 13% when it was administered with paclitaxel .

Pertuzumab, a recombinant humanized monoclonal antibody binding to the HER2 dimerization domain, prevents dimerization of HER2 with other HER receptors (HER3,HER1, and HER4) especially with HER3. Pertuzumab differs from trastuzumab in the epitope binding regions of the light chain; pertuzumab binds to domain 2 ofHER2 essential for dimerization, whereas trastuzumab binds to domain 4 of HER2. Blocking HER2-HER3 dimerization is postulated to be the most clinically relevant action of pertuzumab and this can effectively block her2-mediated cell signaling.

Pertuzumab is indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

The randomized, double-blind, placebo controlled,phase III CLEOPATRA (the CLinical Evaluation OfPertuzumab And Trastuzumab) study involved 808 patients with HER2-positive MBC who had not received prior chemotherapy or biologic therapy, who were randomized to placebo plus trastuzumab plus docetaxel or pertuzumab plus trastuzumab plus docetaxel as first line treatment until disease progression. No additional cardiotoxicity was observed when adding pertuzumab compared to placebo. The incidence of any cardiac disorder as assessed by the investigators was similar in the placebo (16.4%) and pertuzumab (14.5%) arms. Left ventricular systolic dysfunction (LVSD) was observed in 8.3% and 4.4% of placebo and pertuzumab patients, respectively. Left ventricular systolic dysfunction of grade III or higher was reported in 7 (1.8%) patients in the placebo arm and 4 (1.0%) in the pertuzumab arm.

Treatment of breast cancer with pertuzumab plus trastuzumab plus docetaxel as first line treatment until disease progression might be complicated by cardiotoxicity in up to 14.5% of the Patients.

Cardinale et al showed that troponin I (TNI) positive identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

There is very little data about the reversibility and identification of patients at risk for cardiotoxicity of the pertuzumab plus trastuzumab plus docetaxel regimen and of those who will not recover from cardiac dysfunction,this information is crucial. The usefulness of troponin I (TNI) and Brain natriuretic peptide (BNP) in the identification of patients at risk for PT cardiotoxicity and in the prediction of LVEF recovery has never been investigated.

based on this background , this study aim is to evaluate the cardiotoxicity of pertuzumab plus trastuzumab plus docetaxel regimen and the application of troponin I (TNI) and Brain natriuretic peptide (BNP) in this setting.