TEAM Trial: 5 Years of Aromatase Inhibitor Equal to Sequential Therapy

[Hopeful]

Elsevier Global Medical News. 2009 Dec 30, B Jancin

SAN ANTONIO (EGMN) - Five years of upfront aromatase inhibitor therapy for early-stage breast cancer is equally effective for the prevention of recurrent disease as a sequential strategy of 2-3 years of tamoxifen followed by an aromatase inhibitor for the balance of the 5 years of adjuvant therapy, according to an updated analysis of the TEAM study.

For the primary Tamoxifen Exemestane Adjuvant Multinational (TEAM) end point of disease-free survival 5 years post randomization, the rates were 85.7% for the group assigned to upfront exemestane (Aromasin) and a near-identical 85.4% with sequential therapy, Dr. Daniel Rea reported at the San Antonio Breast Cancer Symposium.

"Both of these strategies appear to be reasonable approaches for patients with hormone receptor-positive breast cancer. The choice about which one you're going to use is going to be based on toxicity profile more than efficacy," observed Dr. Rea of the University of Birmingham (U.K.).
TEAM was an open-label randomized trial involving 9,779 postmenopausal women with hormone receptor-positive early-stage breast cancer, roughly half of whom had lymph node-positive disease. It's the only prospective clinical trial adequately powered to test whether 5 years of adjuvant aromatase inhibitor therapy is superior to sequential tamoxifen followed by an aromatase inhibitor. And the answer is "there's absolutely no sniff of a survival difference between the two arms," Dr. Rea said.

There is, however, a major caveat: TEAM includes a large, prospectively planned translational science program. That effort appears to have paid off by identifying promising biomarkers that predict a large subpopulation of patients likely to receive preferential benefit from upfront aromatase inhibitor therapy.

In a separate presentation at the symposium, Dr. John M.S. Bartlett reported on more than 4,300 TEAM participants whose tumor specimens have been analyzed for HER2/3 status.

Twenty-nine percent of the women were found to have HER2/3-overexpressing cancers. Their risk of disease recurrence during the first 2.75 years of the TEAM study - the period when half the patients were on tamoxifen - was the same regardless of which form of endocrine therapy they were on. In other words, HER2/3-positive tumors appear to be partially endocrine insensitive.

In contrast, for the 71% of TEAM subjects who were HER2/3-negative, being on upfront aromatase inhibitor therapy rather than tamoxifen meant they were 31% less likely to develop a recurrence in the first 2.75 years (P = .01). This observation is supported by a similar finding from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (J. Clin. Oncol. 2008;26:1059-65), although the ATAC analysis was retrospective and underpowered due to small numbers, explained Dr. Bartlett of the Glasgow Royal Infirmary.

Next, Dr. Bartlett and his coworkers on the TEAM Pathology Study integrated the data on HER2/3 status with various molecular and clinical markers of early risk of relapse to develop a novel relapse risk score on a 0-40 scale. The score incorporates nodal status, tumor size and grade, patient age, and quantitative HER2 and progesterone receptor measurements.

This score can stratify patients in terms of early recurrence risk from a low of 2% to as high as 35% at 2.75 years. The investigators were able to convert this information into a clinically practical numbers-needed-to-treat (NNT) format. For example, among patients with HER2/3-negative tumors and a risk score of 25, it is estimated that for every 20 patients treated initially with exemestane rather than tamoxifen, 1 extra patient will avoid a cancer recurrence within the first 2.75 years. For patients with risk scores of 10 or 15, the NNTs are 80 and 40, respectively.

Dr. Bartlett said the next step in this project will be to validate the new early relapse risk model in a separate large patient cohort. He added that there is interest in doing so among the key players in the aromatase inhibitor overview analysis collaborative group.

With regard to treatment-related adverse event profiles, Dr. Rea said there were no real surprises. Upfront exemestane was associated with increased rates of the classic aromatase inhibitor side effects, including musculoskeletal pain, osteoporosis, fractures, nerve compression, vaginal dryness, and hypertension. Sequential therapy was associated with higher rates of tamoxifen-related problems: hot flashes, vaginal bleeding, venous thrombosis, and endometrial pathology.

Dr. Rea and Dr. Bartlett are on the speakers bureau and consultants for Pfizer Inc., which supports the TEAM trial.

Hopeful