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Optimising Herceptin-Based Therapy in HER2-Positive Metastatic Breast Cancer: Presented at IBCEF

By Chris Berrie

VIENNA, AUSTRIA -- February 22, 2006 -- Trastuzumab (Herceptin(R)) has now become the standard care for first-line treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, such that is really inappropriate for further trials to be conducted in HER2-positive women without including trastuzumab, according a researcher speaking here at the International Breast Cancer Expert Forum: Milestones in Management, Confidence and Care (IBCEF).

HER2-positive metastatic breast cancer is associated with early disease progression and poor prognosis. Thus, with some 30% of patients with MBC also being positive for HER2 disease, it is essential to provide an early and accurate determination of HER2 status to determine the prognosis and the therapeutic regimen to be followed, said Christian Jackisch, MD, Head Physician, Department of Obstetrics and Gynecology, Klinikum Offenbach, Germany.

In his presentation on February 11^th, Dr. Jackish began by outlining the main pivotal trastuzumab trials that have led to the present recognition of the therapeutic regimen for HER2-positive metastatic breast cancer.

In trial H0648g, the treatment of the HER2 immunohistochemistry-rated (IHC) 2+/3+ patients depended on their status for prior anthracycline treatment, and involved comparisons across doxorubicin/cyclophosphamide (AC) with or without or with trastuzumab (no prior anthracyclines), and paclitaxel with or without trastuzumab (prior anthracyclines).

Dr. Jackish noted that the addition of trastuzumab to paclitaxel resulted in a 40% increased overall survival of the IHC 3+ subgroup, from 17.9 months to 24.8 months.

This has since led to a range of paclitaxel dosing schedules that have been combined with trastuzumab, and some treatment regimens have shown up to an 80% objective response rate (ORR). Similarly, a range of docetaxel regimens have been combined with trastuzumab, and have also achieved up to 80% ORR.

This latter combination was a part of the M77001 trial of first-line trastuzumab administered at a loading dose of 4 mg/kg, then 2 mg/kg/week plus docetaxel 100 mg/m² every 3 weeks for six cycles versus docetaxel alone, for patients with HER2-positive metastatic breast cancer (n = 188).

In that trial, trastuzumab was seen to increase overall survival by 37%, with 22.7 months for docetaxel alone as compared to 31.2 months with the inclusion of trastuzumab. Of note, the data from this trial also showed the importance of assessing cardiac status prior to treatment, and the need to continue such monitoring throughout treatment.

The pivotal trials of trastuzumab therapy indicated very clearly that the combination of trastuzumab with a taxane has a marked clinical efficacy and an acceptable safety profile. At the same time, the trastuzumab/anthracycline combination was also active, but it was associated with higher cardiac event rates, Dr. Jackish said.

Trastuzumab monotherapy was also seen to be an active and well tolerated regimen for these patients with metastatic disease, he added.

Other researchers are also evaluating combinations of trastuzumab and other chemotherapy schedules, including trastuzumab/vinorelbine, which was highly active and well tolerated, with ORRs of around 80%. Another trial investigated trastuzumab/gemcitabine, but without any great success (ORRs <50%), as was the case for a pilot study on trastuzumab/capecitabine (Xeloda(R)) (ORRs <60%).

In addition, triple agent regimens are under study, such as the CHAT trial of trastuzumab/docetaxel/capecitabine that showed a slight reduction in grade III/IV adverse events with the full triple regimen, over that of trastuzumab/docetaxel. Recently, further data has become available from a range of triple combinations that have included trastuzumab, with ORRs that remained consistently in the 50% to 80% range.

With a view to improving cardiac safety, the HERCULES trial researchers evaluated the addition of trastuzumab to epirubicin/cyclophosphamide. Initial analyses of data in this study suggest that the full triple therapy may be less cardiotoxic than double therapy.

In terms of the hormone receptor status, trastuzumab has been seen to be equally effective for hormone-receptor-negative and -positive disease. However, there are a number of trials that will be looking at trastuzumab in combination with hormonal therapy, such as with tamoxifen, exemestane, anastrozole (TAnDEM trial), fulvestrant and letrozole (eLEcTRA trial).

Dr. Jackisch also touched on preclinical evidence that is showing a benefit of trastuzumab beyond disease progression. One example is the MO17038 trial, which is looking at trastuzumab/capecitabine benefits continuing after patient progression on trastuzumab without and with taxane therapy. Similarly, the RHEA trial will be testing trastuzumab use after (neo)adjuvant relapse.

While the standard first-line therapy for HER2-positive patients with metastatic breast cancer, there are other ongoing trials that should provide further options for the use of trastuzumab in these patients.

The conference was sponsored by Roche.


[Presentation title: HER2-positive Metastatic Breast Cancer: Optimising Herceptin-based Therapy.]

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