One of the most difficult challenges facing oncologists is whether to recommend adjuvant chemotherapy in early breast cancer or to spare patients this aggressive treatment. As a result of the widespread use of screening mammography and public awareness, increasing numbers of women are being diagnosed with breast cancer with smaller tumours and no axillary node involvement. According to present guidelines, only about 15–20% of cases are considered low risk and are should not be given adjuvant chemotherapy.1 However, many women are treated regardless of whether they may fall into this low-risk group; consequently, the majority of women with early breast cancer are over-treated, and the benefits of chemotherapy are outweighed by decreased quality of life and long-term risks. In addition, over-use of chemotherapy in breast cancer represents a substantial socioeconomic burden.
At present, clinical decisions are based on prognostic tools such as the Nottingham Prognostic Index2 and Adjuvant! Online,3 which use common clinical and histological criteria (age, tumour stage, hormone receptor expression). However, there is no consensus on which of these tools is the best.
In recent years, molecular markers such as HER2 have been incorporated into treatment paradigms, but breast cancer is a heterogeneous condition and few individual molecular markers have broad clinical application, In 2002, the Netherlands Cancer Institute studied molecular expression in tumour samples from node-negative breast cancer patients, and identified a 70-gene signature associated with poor prognosis.4 This formed the basis of the MammaPrint diagnostic test, which was validated in 295 patients and was found to be superior to all other clinical prognostic factors, clearly defining two distinct groups with excellent prognosis and others with a high risk of recurrence.5 Another independent validation study of 307 found that the MammaPrint outperformed other risk assessment measures.6 In addition, some patients classified as low risk by traditional criteria were classified as high risk according to the MammaPrint assay, meaning that the assay reduces misclassification of patients’ risk.7, 8
As a result of these promising early findings, the large, multicentric, prospective, randomised controlled MINDACT trial (Microarray In Node negative Disease may Avoid ChemoTherapy) was initiated.7-9 This European study involved 6,693 patients who had undergone surgery for early-stage breast cancer. Patients were stratified in terms of recurrence risk using two methods: analysis of tumour tissue using the MammaPrint assay (genomic risk) and using the Adjuvant! Online tool (clinical risk), and then divided into four groups: low risk by both methods (G-low, C-low, n=2,745), high risk by both methods (G-high, C-high, n=1,806), high genomic risk but low clinical risk (G-high, C-low, n=592), and low genomic risk but high clinical risk (G-low, C-high, n=1,550). Patients in the G-low/C-low group were not given adjuvant chemotherapy while G-high/C-high patients were assigned to adjuvant chemotherapy. Patients categorised as G-high/C-low or G-low/C-high were randomised to adjuvant chemotherapy or no chemotherapy (anthracycline or taxane regimens). Patients also received endocrine therapy (tamoxifen for 2 years followed by letrozole for 5 years or letrozole for 7 years).
Data from MINDACT was presented in April 2016 at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans.10 The women categorised as G-high, C-high had the worst outcomes, with a distant-metastasis-free survival rate at 5 years of 90.6%, while those categorised as G-low, C-low had the best outcomes, with a distant-metastasis-free survival at 5 years of 97.6%. However, the most interesting findings of the study were on the women whose risk assessments was discordant according to the two measures. In this large group of patients outcomes were equally good whether or not patients received adjuvant chemotherapy. The distant-metastasis-free survival rate at 5 years was 94.8% in women assessed as C-high, G low, and 95.1% in women assessed as C-low, G-high.
The value of the MammaPrint was clearly shown when examining data from the 3,356 patients who were categorised as C-high: treatment decisions based on MammaPrint reduced the prescription of chemotherapy by 46%. Five-year distant metastasis–free survival for the discordant G-low/C-high group exceeded 94%, whether randomised to chemotherapy or not. Across the entire MINDACT population, the use of MammaPrint led to a 14% reduction in the prescription of chemotherapy compared with the clinical strategy.
In conclusion, the MINDACT trial is the first prospective randomized controlled clinical trial of a breast cancer recurrence genomic assay with level 1A clinical evidence, and has demonstrated that genomics can guide therapeutic decisions in breast cancer.
1. Coates AS, Winer EP, Goldhirsch A, et al., Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015, Ann Oncol, 2015;26:1533-46.
2. D’Eredita G, Giardina C, Martellotta M, et al., Prognostic factors in breast cancer: the predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution, Eur J Cancer, 2001;37:591-6.
3. Ravdin PM, Siminoff LA, Davis GJ, et al., Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer, J Clin Oncol, 2001;19:980-91.
4. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al., Gene expression profiling predicts clinical outcome of breast cancer, Nature, 2002;415:530-6.
5. van de Vijver MJ, He YD, van’t Veer LJ, et al., A gene-expression signature as a predictor of survival in breast cancer, N Engl J Med, 2002;347:1999-2009.
6. Buyse M, Loi S, van’t Veer L, et al., Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer, J Natl Cancer Inst, 2006;98:1183-92.
7. Mook S, Van’t Veer LJ, Rutgers EJ, et al., Individualization of therapy using Mammaprint: from development to the MINDACT Trial, Cancer Genomics Proteomics, 2007;4:147-55.
8. Cardoso F, Van’t Veer L, Rutgers E, et al., Clinical application of the 70-gene profile: the MINDACT trial, J Clin Oncol, 2008;26:729-35.
9. Rutgers E, Piccart-Gebhart MJ, Bogaerts J, et al., The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase, Eur J Cancer, 2011;47:2742-9.
10. Piccart M, Rutgers, E., van’t Veer, L.J. et al, CT039: Primary analysis of the EORTC 10041/ BIG 3-04 MINDACT study: a prospective, randomized study evaluating the clinical utility of the 70-gene signature (MammaPrint) combined with common clinical-pathological criteria for selection of patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes, Presented ay the AACR Annual Meeting 2016, April 16-20, New Orleans, LA, 2016;.