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International Clinical Trials

Mind Altering

Clinicians have long recognised the heterogeneity of human breast cancers (BCs), both for their diverse natural histories – despite identical morphological features – and in terms of their varying responses to treatment.

The exploration of molecular signalling pathways that contribute to cancer initiation, progression and metastasis, and the development of drugs targeted to block these pathways, has provided the opportunity to conduct clinical trials using molecular features to select patients, assign treatment and assess outcomes.

New prognostic markers that can assist oncologists in making treatment decisions for early-stage BC have been introduced, but prospective evaluation of their use in a randomised clinical trial is not yet available. Meanwhile, the tumour node metastasis staging system for BC – an internationally accepted system used to determine the disease stage – is based on the anatomical extent of the tumour, yet gives little insight into BC biology.

Many requirements must be fulfilled before a cancer biomarker can be approved for clinical use with the highest level of evidence, including technical and clinical validation, and assessment of clinical validity.

70-gene Discovery and Validation

MammaPrint® (MP) is a 70-gene signature with the ability to identify early-stage BC patients at risk of distant recurrence, independent of oestrogen receptor status and prior treatment.

The first validation study was undertaken in a series of 295 consecutive women with stage I or II BC and systemically untreated. At 10 years, the probability of remaining free of distant metastases was 50 per cent in the group with a poor-prognosis signature and 85 per cent in the group with a good-prognosis signature. The poor-prognosis signature was by far the strongest independent predictor of the likelihood of distant metastases, with an overall hazard ratio of 4.6 (95 per cent confidence interval, 2.3 to 9.2; p<0.001).

TRANSBIG, a translational BC research network supported by the European Commission, undertook an independent clinical validation of MP in 307 women with N0, systemically untreated BC and a median follow-up of 13.6 years. MP remained an independent significant prognostic factor, stronger than clinicopathological (CP) risk factors (that is, St Gallen criteria, the Nottingham Prognostic Index and Adjuvant! Online) for distant metastasis-free survival (DMFS) and overall survival.

A subsequent study in 241 patients with 1-3 node positive early BC showed that this tool is also a powerful prognostic marker for this population, with 91 per cent DMFS and 96 per cent breast cancer specifi c survival (BCSS) at 10 years for good prognostic signature patients.

Additional studies have further validated MP in other patient populations, including older early BC patients. Finally, the predictive value of MP for response to chemotherapy has been evaluated. These validation studies formed the rationale behind the European Organisation for Research and Treatment of Cancer’s (EORTC’s) MINDACT trial.

Trial Design

MINDACT – Microarray In Node-negative and 1-3 node positive Disease may Avoid ChemoTherapy – is the first international prospective randomised Phase 3 trial to evaluate the clinical utility of a molecular-based signature for adjuvant treatment decision for early BC. It uses the MP classifier, together with commonly used CP criteria, for selecting patients to receive adjuvant chemotherapy.

To ensure a homogenous control arm, a modified version of the Adjuvant! Online including HER2 was used to classify CP risk. After intense discussion, low clinical risk was defined as a 10-year BCSS of at least 92 per cent for oestrogen receptor (ER) negative and 88 per cent for ER positive BC.

The trial hypothesis is that using the molecular profile approach will outperform the usual CP assessment, more accurately assigning adequate risk categories and reducing by 10-20 per cent the number of patients receiving adjuvant chemotherapy without impairment of long-term outcome. Furthermore, MINDACT includes two additional questions designed to evaluate a non-anthracycline-based adjuvant chemotherapy regimen, and to compare the switching and upfront strategies of adjuvant endocrine therapy.

Preparation and Results

In preparation for the trial, a preliminary study was conducted in six European hospitals to test the logistics for real-time gene expression profiling in a multicentre and multinational setting. The collection and shipment of fresh frozen tumour tissue and gene expression profiling were feasible (RNA obtained in 77 per cent of samples, with a successfully hybridised and gene expression signature result in 100 per cent), and the adjustments formed the basis of the MINDACT standard operating procedures.

Due to the complexity of the trial, a predefined first phase comprising the first 800 enrolled patients was planned to ensure feasibility. The proportion of discordant patients, the reduction in chemotherapy prescription by using the genomic signature and compliance to treatment assignment were all in accordance with the trial hypothesis. These results confirmed the feasibility, in a multinational setting, of this logistically complex study.

In order to ensure a high and homogenous level of quality in MINDACT, a quality assurance (QA) programme was put in place. The results of a QA questionnaire for sites showed, among other things, that:
  • The decision to invite a patient to participate in the study was made by specialists/at a multidisciplinary meeting (97 per cent)
  • According to investigator perception, patients were satisfied with their participation in the study (98 per cent)
  • From a pathologist perspective, the logistics and timelines of MINDACT are feasible in clinical practice (79 per cent)
Baseline results of the trial were presented in 2013. From March 2007 to July 2011, 11,289 patients were screened in 112 sites over nine European countries, of whom 6,694 (59 per cent) were enrolled. Patients enrolled had tumour size less than or equal to 2cm (72 per cent) and were more than 50 years old (66 per cent); some 31 per cent of tumours were discordant by genomic and CP risk assessment; and there was a 14 per cent decrease in chemotherapy assignment when using MP. Importantly, genomic stratification only partly overlaps with CP risk – for example, nodal status (0 versus 1-3) was not correlated with MP risk, r=0.01.

Study Significance

International guidelines for the treatment of BC – for instance, St Gallen and the National Comprehensive Cancer Network – recognise the accuracy and reproducibility of first generation multi-gene molecular assays. However, none are currently considered sufficiently validated to be widely used in clinical practice, and their use is reserved for cases where CP factors alone are insufficient to make a decision. The clinical validity and role in clinical practice of these assays is being assessed in large, prospective, randomised studies such as the MINDACT trial (for MP), and a further study, TailorX (for another genomic test, Oncotype DX). The results of both are expected in 2015.

MINDACT is noteworthy because it confirms the logistic ability of the TRANSBIG group to perform a highly complicated study in which pre-surgical frozen tissue was mandatory and a huge number of BC patients were screened and enrolled. The trial is also important as it is the first prospective study aimed at demonstrating that a significant proportion of BC patients can be spared chemotherapy without a detrimental effect on distant relapse-free survival, based on the genomic assessment of risk.

Levels of Evidence

The currently accepted classification of levels of evidence in cancer biomarkers establishes two types of level 1 evidence. Level 1B evidence is achieved when we have positive data from a prospective trial not initially designed to address the clinical utility of a tumour marker, but whose design accommodates for this purpose; a second confirmatory trial of similar design is also required. Level 1A evidence is achieved when we have positive data from a prospective clinical trial aimed at demonstrating the clinical utility of a new biomarker; no confirmatory study is required in this case.

Several retrospective analyses of prospective trials have provided level 1B evidence of the prognostic validity of Oncotype DX and, more recently, the PAM50 subtype predictor and the EndoPredict multi-gene test for BC. MP lacks that level of evidence since it requires frozen tissue that was not available from old trials. The MINDACT trial will hopefully provide level 1A evidence for the clinical utility of MP.

Positive Promise

One in three patients in the trial had discrepant results and would switch adjuvant therapy – from chemotherapy to no chemotherapy and, to a much lesser extent, in the opposite direction – due to the results of MP. If the final MINDACT results are positive, it will mean that chemotherapy and its troublesome side-effects can be safely avoided in a significant proportion of patients. It will also mean that a small but still relevant proportion of patients with apparently low CP risk actually has an aggressive genotype, according to MP, and should be switched to chemotherapy, thus avoiding potentially lethal relapses.

However, all study designs have some weaknesses, and the MINDACT trial is no exception. It is generally accepted that genomic platforms are mainly useful in ER positive/HER2 negative patients, in which the question of adding chemotherapy to hormonal therapy is the crucial one. In the remaining tumour subtypes, the therapeutic dilemmas are different and perhaps should be addressed with different approaches.

The influence of the inclusion of ER negative patients in the MINDACT trial, in which chemotherapy (plus or minus trastuzumab) is the only available adjuvant option, could introduce some background noise in the final results of the trial. But, despite this, MINDACT is an outstanding study whose final results are eagerly awaited.

MINDACT has funding grants from the European Commission Framework Programme VI, the Breast Cancer Research Foundation, Novartis, F Hoffman La Roche, Sanofi-Aventis, the National Cancer Institute, the EBCC-Breast Cancer Working Group, the Jacqueline Sero-ussi Memorial Foundation, Prix Mois du Cancer du Sein, Susan G Komen for the Cure, Fondation Belge Contre le Cancer, Dutch Cancer Society, Association Le Cancer du Sein, Parlons-en!, Deutsche Krebshilfe, the Grant Simpson Trust and Cancer Research UK. Whole genome analysis is provided by Agendia.

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Fatima Cardoso, MD, is Breast Cancer Programme Coordinator at the European School of Oncology and Director of the Breast Unit at Champalimaud Cancer Center in Lisbon, Portugal. She is the current Secretary General of EORTC and Co-Chair of the Advanced Breast Cancer International Consensus Guidelines. After obtaining her medical degree from the University of Porto, Fatima worked at the Jules Bordet Institute in Brussels and MD Anderson Cancer Center in the US. She has also served as the Scientific Director of TRANSBIG.

Miguel Martin is Head of the Medical Oncology Service at the Hospital General Universitario Gregorio Marañón in Madrid, Spain. He is also a Professor of Medical Oncology at the Complutense University of Madrid. Miguel studied Medicine at the University of Valladolid, obtaining his PhD in 1985 and European Certification for Medical Oncology four years later. He is a Founder of the Cancer International Research Group, now named Translational Research in Oncology, and is Chairman of GEICAM, a Spanish breast cancer research group.

Gustavo Werutsky, MD, is Assistant Professor of Medical Oncology at Hospital São Lucas, Brazil (part of PUCRS University) and Scientific Director of the Latin American Cooperative Oncology Group. He was a Medical Fellow of the EORTC from 2008-11, where his fellowship programme was QA in the MINDACT trial.
Fatima Cardoso
Miguel Martin
Gustavo Werutsky
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