The study reviewed here found that treating hormone-receptor-positive, HER2-positive metastatic breast cancer with the hormonal therapy medicine Femara (chemical name: letrozole) AND the targeted therapy medicine Tykerb (chemical name: lapatinib) offered more benefits than Femara alone. These results were presented at the 2008 San Antonio Breast Cancer Symposium.
Hormonal therapy medicines such as Femara often are used to treat hormone-receptor-positive metastatic breast cancers. About one-third of hormone-receptor-positive metastatic breast cancers will respond to hormonal therapy alone.
HER2-positive cancers have too many copies of the HER2/neu gene that makes too much of the HER2 protein. About 1 out of every 4 breast cancers is HER2-positive. Advanced-stage HER2-positive breast cancers that are also hormone-receptor-positive often are treated initially with just a hormonal therapy medicine, but these types of cancers often stop responding to the hormonal therapy medicine.
Researchers think that this lack of response by HER2-positive cancers to hormonal therapy medicines is caused by the HER2 protein. So they wanted to see if combining hormonal therapy with Tykerb, a medicine that specifically targets HER2-positive cancer cells, would make the treatment more effective.
More than 200 women diagnosed with metastatic hormone-receptor-positive, HER2-positive breast cancer participated in this study. The metastatic breast cancer had not been treated before in any of the women. About half of the women received Femara alone as a first treatment, while the other half of the women received Femara and Tykerb.
The results:
The women who got both Femara and Tykerb had side effects commonly associated with each treatment:
Right now, Tykerb is approved by the U.S. Food and Drug Administration (FDA) to be used only in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine) to treat HER2-positive, metastatic breast cancer that has stopped responding to Herceptin (chemical name: trastuzumab), another targeted therapy medicine that targets HER2-positive cancer cells. This study used Tykerb in a way that is not approved by the FDA. So while this research is very promising, more research is needed before Tykerb is used routinely to treat hormone-receptor-positive, HER2-positive metastatic breast cancer.
If you've been diagnosed with hormone-receptor-positive, HER2-positive metastatic breast cancer, you might want to talk to your doctor about this study. You may be able to be part of a clinical trial that does more research on Tykerb and Femara.
Visit the Breastcancer.org Targeted Therapies section to learn about the different targeted therapy medicines, how they work, when they are used, and possible side effects.
SAN ANTONIO, Dec. 15 (MedPage Today) -- For postmenopausal women, the combination of lapatinib (Tykerb) and letrozole (Femara) may control endocrine-sensitive metastatic breast cancer better than letrozole alone, researchers found.
Among patients with hormone receptor- and HER2-positive metastatic tumors, combination therapy more than doubled the median progression-free survival to 8.2 months compared with 3.0 months on letrozole alone (P=0.019), reported Stephen Johnston, Ph.D., of the Royal Marsden Hospital in London, and colleagues at the San Antonio Breast Cancer Symposium here.
This combination, though unapproved for this use, potentially offers an orally active first-line treatment for this group of patients deemed suitable for endocrine therapy based on performance status, sites of disease, and the absence of rapidly progressive visceral disease, he said.
"Previously these patients have been offered an aromatase inhibitor alone," he said, "but now the suggestion is that combined therapy would certainly be a better approach."
The combination appears to be a "very reasonable alternative" with the potential to become a standard of care, said Carlos Arteaga, M.D., of Vanderbilt University and moderator of the press conference at which the findings were presented.
Endocrine resistance, which is associated with activation of growth factor receptors EGFR and HER2, often limits hormonal therapies in metastatic breast cancer, Dr. Johnson said.
Only about a third of metastatic tumors that express estrogen or progesterone receptors or both respond to these treatments, he noted.
To see whether targeting both pathways would overcome this resistance and boost efficacy of hormonal therapies, the researchers tried adding lapatinib, a tyrosine kinase inhibitor that blocks EGFR and HER2.
The phase III study included 1,286 patients with treatment-naive metastatic breast cancer expressing receptors for estrogen, progesterone, or both.
Participants were randomly assigned to letrozole at 2.5 mg daily plus either placebo or lapatinib at 1,500 mg per day.
The primary outcome measure focused on progression-free survival among the subgroup of 219 patients with HER2 positive tumors.
In this hormone receptor- and HER2-positive group, combination therapy improved progression-free survival by 29% (hazard ratio 0.71, P=0.019) with an absolute 3% reduction of in the number of patients who had a recurrence or died compared with letrozole alone (79% versus 82%).
The overall intent-to-treat population had a small but significant improvement in progression-free survival as well (median 11.9 versus 10.9 months, HR 0.86, P=0.026). This suggested that lapatinib may have delayed development of resistance in some patients, although still an exploratory explanation for this benefit, Dr. Johnston said.
For the HER2 positive group, the combined partial and complete response rate was substantially better with letrozole plus lapatinib (37.7% versus 14.8%, odds ratio 0.4, P=0.003).
The clinical benefit rate measuring stable disease improved with the addition of lapatinib to letrozole in this group also (48.7% versus 28.7%, P=0.003), "showing the benefit for the combination in controlling the disease and controlling it for longer than just using endocrine therapy alone."
Neither secondary endpoint was significant in the larger cohort.
These differences between groups "confirm that high HER2 is a mechanism of resistance," Dr. Arteaga said.
The combination regimen was associated with side effects well known for the agents such as low-grade rash and diarrhea, typically managed with dose reduction, interruption, or symptomatic management. The only grade 3 toxicity-diarrhea--among the common adverse events led to study discontinuation in just nine patients.
Notably, no significant cardiac signals appeared, Dr. Johnston said.
The study was sponsored by GlaxoSmithKline. The researchers provided no information on conflicts of interest.
Dr. Arteaga reported no conflicts of interest.
Primary source: San Antonio Breast Cancer Symposium Source reference: Johnston S, et al "Lapatinib Combined with Letrozole vs. Letrozole Alone for Front Line Postmenopausal Hormone Receptor Positive (HR+) Metastatic Breast Cancer (MBC): First Results from the EGF30008 Trial" SABCS 2008; Abstract 46.
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