Overcoming Barriers to Clinical Trials Cooperation: The Breast International Group Example.

Clinical trials cooperation is not a luxury; it is a necessity, now more than ever, first in light of the segmentation of tumors according to their molecular targets-which are being matched to an increasing number of competitive drugs-and second because it is the only chance to maintain academic research centered on addressing patients' needs. In its 21 years of existence, the Breast International Group, an umbrella organization supporting the activities of 54 member groups across six continents, has been confronted with challenges that include (1) keeping trust and motivation within the network; (2) improving the interface between academia and industry; (3) improving patient involvement and trust in clinical trials; and (4) fundraising for noncommercial research. We describe how these challenges have been addressed so far, with the hope of empowering the next generation of clinical investigators.

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Better translation from bench to bedside: breakthroughs in the individualized treatment of cancer.

This article reflects on progress made in recent years with respect to bench-to-bedside research in breast cancer. It shows how the advent of molecular oncology-accompanied by high-throughput experimental methods and "omics" technologies-has led researchers to realize that breast cancer is a heterogeneous disease for which a "one size fits all" approach to patient treatment is no longer optimal. This, in turn, has contributed to a change in thinking about clinical trial design. Using several examples of clinical trials being run under the umbrella of the Breast International Group, including the recently launched Microarray In Node-negative Disease may Avoid ChemoTherapy study and Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization study, the article looks at how translational research and biological specimen collection has become a central component of clinical research design in a relatively short period of time. This, plus an evolution in research culture that has resulted in increased international collaboration among research networks, groups, and centers, will arm researchers with the tools needed to develop truly individualized cancer treatments for patients in the future.

[The new generation of breast cancer clinical trials: the right drug for the right target]. / La nouvelle génération des études cliniques sur le cancer du sein: la bonne drogue et la bonne cible.

The principal mission of the Breast International Group (Big), Transbig, and the Breast European Adjuvant Study Team (Breast), all located at the Jules Bordet Institute in Brussels, is to accelerate and facilitate the initiation and conduct of large and difficult breast cancer clinical trials. This is made possible through the excellent network of research groups, scientists, physicians and many other collaborators deeply committed to academic clinical and translational research. A clear example of this collaboration is the HERA trial (Herceptin Adjuvant trastuzumab in HER2 positive early breast cancer) that contributed to a change of clinical practice and improved the prognosis for this particular patient population. In addition, there is an important new generation of adjuvant trials, for example, Mindact, which is evaluating the use of microarray technology in treatment decision making, and the Altto and Neo-Altto studies, which have just started and are evaluating lapatinib, a small tyrosine kinase molecule given either adjuvantly or neo-adjuvantly, alone, sequentially or in combination with trastuzumab, in patients with HER2 positive early breast cancer. The latter studies, with their strong translational research component, aim to determine which tumour profiles will best benefit from lapatinib as opposed to treatment with trastuzumab alone.

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)