Trastuzumab (Herceptin)

Humanized monoclonal antibody against the extracellular domain of the HER-2 protein-inhibits downstream, signaling and promotes antibody dependent cellular cytotoxicity

Blocks signaling via HER-2 homodimers.

Blocks HER2 receptors outside of the cell, preventing growth signal.

Binds to subdomain IV of the HER2 extracellular domain and has anti-tumor effects by blocking HER2 cleavage thus stimulating antibody-dependent, cell mediated cytotoxicity and inhibits ligand-independent, HER2 mediated mitogenic signaling.

Inhibits the proliferation of human tumor cells that over express HER2.

Only patients with breast cancer tumors carrying the HER-2 protein expression with a 3+ immunochemistry score benefit from treatment with Trastuzumab.

May cause left ventricular systolic dysfunction and occasionally congestive heart failure in a small percentage of patients.

Can cause cardiomyopathy, and most patients should receive cardiac monitoring during therapy.

Improves overall survival in patients with HER-2 positive metastatic breast cancer and disease free and overall survival in HER2 positive early stage breast cancer.

Neoadjuvant setting, the addition of trastuzumab chemotherapy doubled the probability of achieving the pathological complete response.

In patients with HER2 positive early stage breast cancer, it reduces the overall mortality by 1/3.

Incidence and severity of cardiac dysfunction increased in patients treated with Trastuzumab and combination chemotherapy with an anthracycline and cyclophosphamide.

Most frequent clinical manifestation of cardiotoxic effects is diminished systolic left ventricular function measured with left ventricular ejection fraction.

The development of cardiac dysfunction with its use negatively effects cardiac outcomes and limits therapeutic opportunities.

Cardiac dysfunction increased by a factor of four, including CHF, especially when used in combination with anthracycline based regimens.

Cardiac toxicity can range from an asymptomatic fall in left ventricular function in 4-18% of recipients, to moderate to severe heart failure in 2-4% of recipients.

CHF occurs in 1-3% of patients of patients in clinical trials.

CHF develops in nearly 30% of patients when trastuzumab is given concurrently with anthracycline

The rate of premature discontinuation secondary to cardiotoxicity is reported to be up to 25%.

Recommendations are to withhold the drug in patients with a significant asymptomatic decline in left ventricular function and in patients in whom the LVEF fails to normalize after two months, permanent discontinuation is recommended.

LVEF monitoring should occur every three months during and upon completion of the drug.

Is unable to penetrate the blood-brain barrier.

When administered weekly or every three weeks alone or with chemotherapy is beneficial in patients with HER2 positive breast cancer.

Trastuzumab when added to chemotherapy doubled the proportion of patients achieving a pathological complete response when compared with chemotherapy alone in HER2 positive early stage operable breast cancer patients as neoadjuvant therapy.

Less than a third of patients with HER2 positive disease benefit from this agent.

Single agent treatment response rate 35% in first line treatment of metastatic breast cancer, and a response rate of 15% for second line treatment.

Use in patients associated with increased frequency of brain metastases.

Progression of disease inevitably occurs during or after completion of treatment, with majority of patients developing resistance to the drug within one year of the initiation of therapy.

In a study involving 479 women with metastatic breast cancer overexpressing HER2 comparing chemotherapy to chemotherapy plus Trastuzumab resulted in higher response rates in the latter group (Slamon).

The addition of trastuzumab to chemotherapy significantly improves rates of objective response, response duration, and time to progression, 56%, 58%, and 65% improvement, respectively, as well as a 30% improvement in the rate of overall survival among patients with first line metastatic breast cancer disease.

In combination with paclitaxel or doxirubicin/cyclophosphamide has a greater activity in breast cancer than chemotherapy alone.

A metanalysis confirmed  that breast cancer recurrence and mortality can be reduced by 1/3  by adding one year of trastusumab to adjuvant chemotherapy in patients with early stage, HER2 positive breast cancer.

Addition to first line treatment with anthracycline or taxane based treatment in HER-2 positive patients associated with increased time to progression 7.4 vs. 4.6 months, and a higher response rate of 50% vs. 32% and a longer duration of response 9.1 months vs. 6.1 months.

Cardiotoxicity reported in 1.4 % of patients who received the agent as a single drug for metastatic disease.

1-4% of treated patients have heart failure and 10% have decreased cardiac function.

Cardiac toxicity with doxirubicin is significant and persists more than 18 months, the last date of follow-up.

Use after anthracycline treatment is a major risk factor for the development of CHF.

Cardiac dysfunction is often reversible when the drug is discontinued and with the initiation of standard medical treatment for congestive heart failure.

Signaling pathways P13K and hsp90 may account for resistance in breast cancer treatment with trastuzumab.

In early breast cancer with HER2 positive disease trastuzumab given with or without chemotherapy reduces early risk of recurrence by approximately 50%, with an almost 20% absolute improvement in predicted 4-year disease-free survival.

NSABP-31 and NCCTG-N9831 trials showed that trastuzumab given concurrently with paclitaxel reduced breast cancer recurrence by approximately 50% in patients given adjuvant therapy.

Adjuvant trastuzumab alone or with predominantly anthracycline based regimens reduce recurrence rate by approximately 50%, and improved survival rate of approximately 30%.

In adjuvant studies trastuzumab when used with anthracyclines CHF was increased by a factor of 4-5, and an even larger proportion of patients had subclinical loss of left ventricular function.

In the first line metastatic setting, 27% of patients receiving concurrent doxorubicin, cyclophosphamide, and trastuzumab develop either symptomatic or asymptomatic cardiac dysfunction (Slamon DJ et al).

First time use with chemotherapy results in longer median survival than with chemotherapy alone, suggesting synergy of trastuzumab when added to chemotherapy (25.4 vs. 20months (Baselga).

The HERA trial revealed that after completion of adjuvant chemotherapy the administration of trastuzumab reduced the risk of breast cancer recurrence.

After a median follow-up 8 years the HERA study showed that 2years of of trastuzumab vs 1year after adjuvant chemotherapy in HER2 positive early breast cancer showed no improvement in disease survival, and 1year treatment remains the standard of care.

Four trials with more than 13,000 women with HER2 overexpression with early stage breast cancer and have received adjuvant trastuzumab have a reduced 3-year risk of recurrence by approximately 50%.

The addition of adjuvant trastuzumab significantly improved disease free and overall survival among women with HER2 positive breast cancer in a study of 3222 women with early stage BC comparing doxorubicin and cyclophosphamide followed by docetaxel, the same treatment plus trastuzumab, or docetaxel plus carboplatin plus trastuzumab: Estimated disease free survival at 5 years 75%,84%, and 81%, respectively and overall survival 87%,92%, and 91%, respectively (Slamon D et al).

In the Herceptin Adjuvant (HERA) study evaluating a sequential regimen of trastuzumab monotherapy after completion of chemotherapy, the rate of severe congestive heart failure was 0.8%, and 3.6% of individuals experienced a decrease left ventricular ejection fraction at a median followup of 3.6 years (Proctor M at al).

NSABP-31 study revealed cumulative increase in cardiac toxicity of 3.3% compared to control group, with increased risk in older patients and those given doxorubicin in proximity to trastuzumab.

At 7 years the NSABP-31 study which randomly assigned patients to receive an anthracycline and taxane based chemotherapy alone or with trastuzumab: the cumulative incidence of cardiac events at 7 years was 4% in the trastzumab arm vs 1.3% in the non-trastuzumab arm.

1.8% of doses associated with an infusion related reaction: vast majority of infusion reactions occur with the first infusion, are mild and easily managed (Thompson LM et al).

In the above study LVEF recovered to 50% or greater in more than that of the patients that experienced a cardiac event or asymptomatic LVEF decline.

Incidence of cardiac failure in the HERA study was 1.7% and the incidence of severe congestive heart failure was 0.5%.

A subgroup of patients with elevations of serum troponin I or more likely to develop transtuzumab induced cardiotoxicity, less likely to recover from its effects (Cardinale D et al).

Patients with an elevated troponin I level have a 25 fold increase in risk for major cardiac adverse events (Cardinale D et al).

Prior anthracycline exposure increases the risk of trastuzumab induced cardiotoxicity.

Cumulative anthracycline dosage increases the risk of trastuzumab induced cardiotoxicity.

Elevations of troponin I were observed exclusively in patients previously treated with anthracyclines (Cardinale D et al)

Cardiotoxicity of trastuzumab is different than that from anthracyclines in that it is not cumulatively dose-related.

Cardiotoxixity not associated with myocyte destruction.

Cardiotoxicity is usually reversible.

In a population of 231 patients receiving docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 with Trastuzumab for adjuvant chemotherapy for HER2+ breast cancer only one patient had a significant drop in left ventricular ejection fraction to 40% indicating an acceptable toxicity profile for lower risk patients with HER2+ breast cancer (Jones).

In a randomized study evaluating Lapatinib alone or in combination with Trastuzumab in 296 patients with HER2+ metastatic breast cancer whose disease has progressed while being treated with Trastuzumab: the combination improved median progression free survival 8.4 weeks vs. 12 weeks for the combination group, but the overall survival and response rates were similar (O’Shaughnessy J).

In a phase II study CHER-LOB trial stage II orII breast cancer patients HER2+ who received chemotherapy prior to surgery for stage II or III BC responded better to treatment with a combination of trastuzumab and tyrosine kinase inhibitor lapatinib then with treatment with either lapatinib or trastuzumab alone with chemotherapy: A complete pathological response was noted in 28% of patients in the trastuzumab only arm, 32% in the lapatinib only arm and 48% in the combination arm (Guarneri V et al).

Patients who develop CHF on trastuzumab respond very well to treatment with rare deaths.

Adding trastuzumab to standard chemotherapy for advanced disease increased survival by 26% in patients that expressed high levels of HER 2 protein compared to chemotherapy alone.

Combination of lapatinib plus trastuzumab compared to lapatinib alone in women with HER2+ metastatic breast cancer that had progressed on multiple lines of treatment: combination superior in progression free survival compared to lapatinib alone, median overall survival in the combination arm 60.7 weeks compared to lapatinib alone at 41.4 weeks (Blackwell KL).

Resistance affects most patients who receive the drug as treatment for metastases to breast cancer, and to approximately half of the patients who receive it as adjuvant therapy.

Dysregulation of the mTOR pathway, either through P13k or PTEN it may be one of the causes of drug resistance.

Proposed mechanisms of drug resistance include: Upregulation of insulin-like growth factor-1 receptor (IGF-1R) expression, expression of truncated HER2, increased expression of phosphoinositide-3-kinase (PI3K), increased expression of v-akt murine thymoma viral oncogene homolog1 (AKT), mutations in genes for PI3K or AKT, and loss or reduced expression of phosphatase and tensin homolog (PTEN ) and activation of AKT/m-TOR pathway (Andre F et al).

The combination of Everolimus, an mTor inhibitor nd trastuzumab Have a role in the treatment of HER-2 overexpressing breast cancer.

In a phase 3 study randomized Clinical Evaluating of Pertuzumab and Trastuzumab (CLEOPATRA) trial of 800 meet patients with metastatic HER2 positive breast cancer adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy stated progression free survival by a median of 6.1 months compared to the combination therapy plus placebo.

In adult B-cell ALL refractory HER2 receptor positive patients refractory to treatment have a partial response to trastuzumab of 13%.

Concomitant use of angiotensin II-receptor inhibition as a protective agent against a decreased LVEF is not efficacious.

ACE inhibitors and beta-blockers are helpful in reducing hear pump weakness in patients on Herceptin MANTICORE trial).

Currently clinical recommendations include assessing left ventricular function before the initiation of therapy, routine left ventricular ejection fraction monitoring every 3 months during treatment, and discontinuation of therapy based on the changes of LVEF.

The FDA has approved subcutaneous use of trastuzumab and hyaluronidase-oysk injection in combination with chemotherapy for the treatment of select patients with HER2-positive early breast cancer, and alone or in combination with paclitaxel in patients with metastatic HER2-positive breast cancer who have received at least 1 prior chemotherapy regimen (Herceptin Hylecta).

The subcutaneous trastuzumab studies revealed comparable rates of efficacy and safety compared with standard intravenous use of trastuzumab.

Leave a Reply

Your email address will not be published. Required fields are marked *