ABSTRACT
MammaPrintMINDACT (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy), as illustrated in Fig. 14.1, is a prospective randomized study comparing the 70-gene signature MammaPrint assay with the common clinical-pathological criteria in selecting patients for adjuvant chemotherapy in breast cancer with 0-3 positive nodes (EORTC Protocol 10041 -BIG 3-04; https://www.eortc.be/services/unit/mindact/MINDACT_websiteii.asp; ClinicalTrials.gov Identifier: NCT00433589) [30, 31]. The objective of MINDACT is to test whether patients with a low risk signature may
SCREENING
TRIAL DESIGN
Figure 14.1 Schema of MINDACT study. Abbreviations: PIS, patient information sheet; IC, informed consent; T: tumor stage; N: nodes; M: metastasis; HR: hormone receptor. safely be spared the toxicities of chemotherapy without affecting their survival. The study is complex in that it further tests which of two chemotherapy treatments offers better survival and which of two endocrine regimes is more effective. Each enrolled breast cancer patient will be assessed using both MammaPrint and conventional
prognostic tools. For most women, the results of the two tests are expected to be the same. Chemotherapy, either anthracycline-or docetaxel-based, will be offered to those who are categorized as high risk by both assays. It will not be offered if they are shown to be at low risk by both assays. Women for whom the conventional and MammaPrint tests do not agree will be randomized according to conventional or MammaPrint test results and allocated to either adjuvant chemotherapy or no adjuvant chemotherapy. Additionally, all women who are estrogen receptor positive will be offered one of two endocrine treatment regimens: 7 years of single agent letrozole or the sequential strategy of 2 years of tamoxifen followed by 5 years of letrozole. It is hoped that not only will 10% to 20% of patients be spared treatment but that there will be considerable savings for the national health services. The MINDACT was first activated in the Netherlands on March 22, 2007, and was amended to increase the sample size to 6600. By July 2011, the study reached the accrual goal with 6700 breast cancer patients have been enrolled from 119 participating institutions in 9 European Countries. From 119 participating institutions in 9 European Countries. Similarly to the TAILORx trial in the United States, the MINDACT study has progressed well in accruing patients, suggesting the general acceptance of using new molecular risk assessment tools in guiding clinical decisions for treatment planning. The results from these two studies are highly anticipated. 14.6 Biologic Implication of MammaPrint
14.6.1 Understanding of Tumor BiologyIt is interesting that a prognostic signature could be developed using the transcriptional profile of primary breast tumors. This suggests that the metastatic potential is inherently expressed in the initial tumor rather than being acquired at a later stage. A recent report provides functional annotation of the 70 genes in the MammaPrint with the hallmarks of cancer [32]. Figure 14.2 illustrates the genes that are known to be functionally involved in recurrence, such as signal transduction and cell cycle, invasion, metastasis and angiogenesis genes that are found to be significantly upregulated
in the poor prognosis signature. Many of these candidate genes should be investigated to test their feasibility as new therapeutic targets. It is interesting to note that individual genes that have been previously correlated with disease outcome, such as cyclin D1, ERS1, HER2, c-myc, UPA and PAI-1 are not present in the 70gene MammaPrint profile. This is most likely due to the overlap and redundancy inherent in biological processes as well as our own lack of knowledge. Indeed, genes regulated by ERα and HER2 are represented in the 70-gene profile. A network association map of the 70 genes that comprise MammaPrint shows that key players in cancer, such as p53, Rb, c-myc, Jun and CDKN2, are central regulators although their change in expression is not integral to the profile [32]. It is known that clinical factors, such as co-morbidities (e.g., diabetes, chronic inflammation, etc.) affect patient’s risk of tumor recurrence and survival. Currently, it is not known how these clinical factors affect the results of 70-gene expression in MammaPrint test.
