MINDACT Trial Research Articles

WS9-1 - Individualization of Breast Cancer Treatment: Opportunities and Challenges in Asia

ABSTRACT Recommendations for adjuvant and palliative treatment in breast cancer patients are based on a clinician's estimated risk assessment for relapse, death, and the likely benefit of systemic treatment. However, predicting the absolute benefit of systemic therapy for an individual woman with breast cancer is a complex issue. Western patient-based prediction system may not be suitable for Asian breast cancer patients who are associated with younger age and worse prognosis than Western patients. For the individualized treatment, there are several ways of approach for the breast cancer patients. First, screen the patients for the specific targets with available target-specific drugs. The good model is the anti-HER2 drug treatment of the HER2 amplified or over-expressing patients. Second, for chemotherapeutic agents, trials to use the biomarker in predicting poor prognosis from chemotherapy resistance are under study. These markers are being studied using polymorphism, copy number change, genomics study or combination of these. There is no specific data yet whether there are ethnic differences in chemotherapy resistance or biomarker expression. Third, use high-throughput technology to select the patients to better determine which patients group really needs specific treatment. The best example is the MINDACT trial. One possible limitation is that the biomarker may differ between early-stage and advanced stage. In current trials, biomarkers are determined from the original diagnostic tissues and may not reflect the relapsed tumor status, and thus hamper the decision making for the personalized treatment. As there are so many developed targeted agents, it is a real issue how we can combine the targeted agents or to find the best chemotherapy partner to targeted agent to a specific patients. In lung cancer, the BATTLE trials are being done toward realizing personalized cancer therapy by integrating real-time molecular markers. Like this, translational research and biomarker-driven clinical trials are warranted for the Asian breast cancer patients for the personalized treatment.

P1-07-06: High Concordance of Protein (by IHC), Gene (by FISH; HER-2 Only) and Microarray Readout (by TargetPrint) of ER/PR/HER2: Results from the MINDACT Trial.

Abstract Background Previously, the micro-array readout of ER, PR and HER2 by TargetPrint was shown to be strongly correlated with high quality immunohistochemistry (IHC)/FISH assessment, especially for ER and HER2. Concordance rates were 93% (k=0.79) for ER; 83% (k=0.65) for PR and 96% for HER2 (k=0.88) in 636 patients (Roepman et al., Clin Cancer Res, 2009). This study analysis was undertaken to further determine the correlation of microarray readout with IHC/FISH assessment both locally and centrally determined in the 1st 800 pts enrolled in the MINDACT trial. This work is essential to determine the quality of biological data in the two risk assessment methods used in MINDACT based upon which adjuvant chemotherapy decision is made, in order to exclude bias. Methods: ER/PR/HER2 IHC assessment was performed on the 1st 800 primary breast cancers (BC) of pts enrolled in the MINDACT study. The assessment was performed locally at each center (n=800) and by central review at the laboratory of the European Institute of Oncology (n=626). A tumor was classified positive for ER and PR when 1% of tumor cells showed positive staining. HER2 IHC status was scored as 0, 1+, 2+ or 3+; a score of 3+ was considered positive. In 2+ cases FISH was performed to assess final HER2 status. Gene expression data for ER, PR and HER2 were obtained by TargetPrint stratified as receptor positive or negative using previously determined and validated thresholds for ER, PR and HER2 mRNA levels (n=800). Results: Comparison of local assessment (IHC & FISH for HER2) with central review indicated highly similar results for receptor readout with a concordance of 98% (k=0.90) for ER; and 96% for HER2 (k=0.80) and slightly lower for PR (90% (k=0.72)). Comparison of central assessment (IHC & FISH for HER2) with micro array readout by TargetPrint indicated highly similar results for receptor readout with a concordance of 97% (k=0.88) for ER and 95% for HER2 (k=0.76). For PR the concordance was lower but still quite acceptable (85% (k=0.62)). Conclusion: Local and centrally assessed ER, PR and HER2 status in the first 800 MINDACT patient samples indicate a high level of quality for pathology in the local participating hospitals. These results exclude any bias induced by a lower quality of “traditional” pathology results as compared to the centrally assessed MammaPrint, both used for risk assessment and adjuvant chemotherapy decision in the MINDACT trial. The microarray-based assessment of ER, PR and HER2 gives results comparable to IHC & FISH and provides an objective and quantitative assessment of tumor receptor status. These results indicate that TargetPrint can serve as a second pathology assessment for locally assessed parameters, especially since TargetPrint is part of a multi-profile platform for breast cancer treatment management. This work was funded by the Breast Cancer Research Foundation and the EU Framework Program VI. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-06.

The EORTC 10041/BIG 03-04 MINDACT trial is feasible: Results of the pilot phase

BackgroundThe MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. MethodsMINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered. ResultsDuring the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P<.0001). Compliance with the treatment decision was high (>92%). ConclusionsThe logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.

Clinical application of genomic profiling in breast cancer and the TAILORx trial

Abstract Breast cancer is characterized by clinical and molecular heterogeneity. Microarray-based gene expression has identified distinct expression profiles associated differing prognosis and response to therapy. Newer technologies now permit evaluation not only of gene expression, but also single nucleotide polymorphisms, gene copy number, genomic mutations, and epigenomic or microRNA patterns that modulate gene expression. These state-of-the-art molecular approaches offer new insights into the pathogenesis of breast cancers, and offer the promise to improve the prevention, diagnosis, and management of the disease. Although many gene expression assays have been shown to provide prognostic information that is complementary to classical clinicopathologic features, the clinical utility of such assays is uncertain — that is, how do the results alter patient care, and do patients benefit from that change? Most attention has focused on using these assays to reduce overtreatment in patients with estrogen-receptor positive, lymph node negative breast cancer, which accounts for about one-half of all breast cancers, and about 8% of all cancers in the United States. Evidence suggest that some assays do have clinical utility when used appropriately, usually by reducing overtreatment with chemotherapy in patients who may otherwise have an excellent prognosis with local therapy plus endocrine therapy alone — or “treatment sparing”. Other potential examples of clinical utility include “treatment selection” (selecting individuals for chemotherapy when standard clinicopathologic features would have suggested otherwise) and “treatment direction” (selecting individuals for chemotherapy when clinicopathologic features suggested therapeutic equipoise). There are three breast cancer clinical trials which have integrated multiparameter assays into the clinical decision making, including the TAILORx and CHORUS trials (which use the 21 gene assay) and the MINDACT trial (which uses the 70 gene assay). The results of these trials will inform us regarding the clinical utility of these assays, and provide a valuable resource for evaluating other clinical cancer tests in the future.

Use of a genomic test (MammaPrint™) in daily clinical practice to assist in risk stratification of young breast cancer patients

Breast cancer as a heterogeneous disease demands reliable tools in order to identify those patients who most likely will benefit from receiving adjuvant treatment, such as chemotherapy. The MammaPrint test was established on the basis of a 70-gene expression profile. In this prospective study, the adaptation of MammaPrint™ into clinical work-up procedures was investigated in 56 patients with an average age of 45 years treated at a general hospital in Germany between 2004 and 2008. To assess the accuracy of MammaPrint in this younger patient group, a meta-analysis was performed on a subgroup from previously described retrospective studies (n = 689). 44 patients had MammaPrint results and were eligible for the analysis. The results revealed a low risk result in 29 patients and a high risk result in 15 patients. Using St. Gallen 2007 guidelines for risk assessment, the numbers were 4 for low risk and 6 for high risk, respectively, while 34 patients were classified as intermediate risk. In the group of women with intermediate risk, MammaPrint assigned 23 patients to low risk and 11 to the high risk group. In the meta-analysis of retrospective studies, 10 year overall survival for the low and high MammaPrint groups was 90.2 and 65.2%, respectively. Using gene expression analysis as additional tool, patients with an intermediate clinical risk can be accurately separated into low and high risk groups. The gene expression analysis provides more accurate information on recurrence risk compared to conventional clinicopathological criteria and thus may provide additional guidance in daily clinical practice in future. Results of further prospectively designed studies like the MINDACT trial will confirm the retrospective analysis and will determine how both low and high risk patients can best be treated.

444 The EORTC 10041/BIG 03–04 MINDACT trial is feasible: first results of the pilot phase

444 The EORTC 10041/BIG 03–04 MINDACT trial is feasible: first results of the pilot phase

The 70-Gene Profile (MammaPrintTM) Is an Independent Predictor of Breast Cancer Specific Survival for Women 65 Years of Age or Older.

Abstract Background: One-half of all new breast cancer diagnoses occur in women age 65 years or older. In this age group, the use of adjuvant chemotherapy is largely influenced by co-morbidity and little is known about the applicability of prognostic multi-gene assays. The 70-gene profile (MammaPrint) is an independent prognostic indicator in early breast cancer, however, its performance in women with breast cancer 65 years or older has not been systematically studied.Methods: Women 65 years or older who were diagnosed at the Jules Bordet Institute and the Netherlands Cancer Institute between 1987 and 2003 with primary breast cancer with 0-3 involved lymph nodes who received either no adjuvant systemic therapy or adjuvant hormonal therapy alone were selected. MammaPrint test results were compared with clinical-pathological risk assessment using Adjuvant!Online.Results: Of 204 women aged 65 years or older (median age 70 years), 129 (63.2%) were classified as genomic low risk and 75 (36.8%) as genomic high risk. After a median follow-up of 8.6 years (range 0.3-17.9), the 5- and 10-year breast cancer specific survival (BCSS) for the genomic low risk group was 96% (SE 2%) and 86% (SE 4%) versus 82% (SE 4%) and 66% (SE 6%) for the genomic high risk group (log-rank p=0.001). In univariate analysis, MammaPrint was prognostic for 5-year BCSS (HR=5.0, 95%CI 1.8-14.1, p=0.002) and 10-year BCSS (HR=3.1, 95%CI 1.6-6.0, p=0.001). In a multivariate model adjusted for 10-year risk predicted by Adjuvant!Online, MammaPrint was independently prognostic for 5-year BCSS (HR=4.4, 95%CI 1.6-12.7, p=0.005) and 10-year BCSS (HR=2.5, 95%CI 1.3-5.0, p=0.009). As in prior validation series, the performance of MammaPrint was time dependent, with improved prognostication for early BCSS (≤5 years).Conclusion: Although a smaller proportion of breast cancers diagnosed in women 65 years or older are classified as high-risk by MammaPrint, it is an independent prognostic indicator that may be useful to select patients that can safely forego adjuvant chemotherapy. Additional data from patients over 70 years of age will be available at the time of the meeting. If these data are confirmatory, the ongoing prospective MINDACT trial will be amended to include older women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4049.

Anwendung von Genexpressionssignaturen beim Mammakarzinom

In Erweiterung zu den klinischen und histopathologischen Faktoren konnten die Genexpressionsanalysen des Mammakarzinoms mit teilweise sehr unterschiedlichen Signaturen unser Wissen um die Prognoseabschätzung dieser heterogenen Erkrankung deutlich erweitern. Obwohl die Ergebnisse prospektiv randomisierter Studien noch nicht vorliegen, sind die bisher vorliegenden Daten zur Validierung der Gensignaturen schon sehr beeindruckend. So hat das Expertenpanel der St.-Gallen-Brustkrebskonferenz von 2009 mehrheitlich die Verwendung der Gensignaturen unter bestimmten Umständen empfohlen. Derzeit sollten die Entscheidungen zur weiteren Therapieempfehlung einer an Brustkrebs erkrankten Frau aber weiterhin auf der sorgfältigen und umfassenden Evaluation der klinischen und histopathologischen Daten beruhen. Aber innerhalb von zwei international durchgeführten wissenschaftlichen Studien (für Europa die MINDACT-Studie) kann die Genexpressionsanalyse betroffenen Patientinnen angeboten werden.

Design of new protocols. Role of molecular biology units?

The majority of current major advances in the management of main human malignancies including breast, colorectum and head and neck result from the introduction of targeted therapies. An optimal application of targeted therapy needs a knowledge for the tumoral status of the target itself. It is also interesting to dispose of biological informations resulting from the interactions between treatment and target (biological proof of the concept). These informations are at the basis of the conception of new clinical protocols in oncology. In this context the role of molecular biology units is determinant. Examples of concrete applications of this strategy will be detailled particularly for the MINDACT Trial in breast cancer and for the KRAS status in the setting of EGFR targeting therapies in advanced colorectal cancer.

Minimising oncological treatment of early breast cancer

Recommendations for adjuvant systemic therapies are based on estimates of life expectancy (prognostic markers) and of benefit to therapy (predictive markers). The oestrogen receptor is a classic predictive marker guiding use of anti-oestrogen therapy, and expression profiling appears to select patients more or less likely to benefit. Expression profiling is also under evaluation as a prognostic marker to identify patients who do not need cytotoxic chemotherapy (MINDACT trial). Biological therapy with trastuzu-mab is prescribed on the basis of a predictive test for over-expression of the target growth factor receptor protein, HER2. The ER-PR-HER2-subgroup identifies patients who may benefit selectively from platinum compounds. In radiotherapy, there is also a trend towards delivering fewer, larger fractions of breast radiotherapy to a lower total dose than the historical standard 50 Gy in 25 fractions. Partial breast radiotherapy is under test as a safe and effective alternative to whole-breast radiotherapy for women with low-risk disease, a measure that is also likely to reduce iatrogenic morbidity in long-term survivors. Finally, the identification of subgroups in which radiotherapy can be safely withheld remains a research priority, with age as the single most powerful factor predicting risk of local relapse.

The 70-gene profile is a powerful predictor of disease outcome in breast cancer patients with 1–3 positive lymph nodes

In multifocal breast cancer, guidelines recommend basing adjuvant systemic treatment decisions on characteristics of the largest lesion, disregarding multifocality as an independent prognosticator. We assessed the association between multifocal disease and both the 70-gene signature (70-GS), and distant metastasis-free survival (DMFS) in clinical low-risk breast cancer patients enrolled in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT) trial.The analysed population consisted of enrolled patients in the MINDACT trial with clinical low-risk disease, defined by a modified Adjuvant! Online cut-off for the 10-year risk of recurrent disease or death. Eligibility criteria of MINDACT dictate that patients with multifocal disease could be included if the different lesions had similar pathological characteristics. The presence of multifocal disease was deducted from the case report form (CRF)-question for sum of diameter for all invasive tumour foci. Clinicopathological characteristics and gene expression of patients with unifocal and multifocal (largest lesion) disease were compared. Subsequently, the association between multifocal disease and the 70-GS was evaluated as well as the association between multifocality and 5-year DMFS.The study included 3090 clinical low-risk patients with unifocal and 238 patients with multifocal disease. Apart from a higher prevalence of lobular tumours (21.8% versus 10.8%, by local pathology), we did not observe differences in baseline characteristics between multifocal and unifocal tumours. Patients with multifocal tumours were more likely to be at high genomic risk as compared to patients with unifocal tumours (22.7% versus 17.3%, odds ratio [OR] 1.45, 95% confidence interval [CI] 1.02–2.07, P = 0.038). We did not find a significant association between tumour focality and DMFS (97.1% for unifocal versus 96.9% for multifocal, hazard ratio [HR] = 1.55, 95% CI 0.68–3.46, P = 0.172), nor a signal for a potential interaction between the prognostic effect of the 70-GS and focality of the tumour regarding DMFS.In the group of clinical low-risk MINDACT patients, multifocal tumours were more likely to have a high-risk 70-GS profile compared to unifocal tumours. We did not observe a significant interaction between multifocality and the 70-GS with respect to survival without distant metastasis in these patients.

2 INVITED Moving cancer treatment into the 21st century

One of the main challenges in oncology today has become to distinguish accurately between those patients who need adjuvant treatment and those who do not. This, together with the identification of the best type of therapy for the individual patient and the development of drugs targeting specific characteristics of tumour cells, are the goals of treatment tailoring or personalized medicine.The MINDACT trial (Microarray In Node negative Disease may Avoid ChemoTherapy) was recently launched with the aim of prospectively validating the superior performance of a new prognostic RNA-based tool – the Amsterdam 70-gene profiler MammaPrint™, in order to implement its use in clinical practice later on. This manuscript shortly reviews the rational, design and logistics of MINDACT.

Expression profiling as a prognostic and predictive factor in breast cancer

Microarray gene expression profiling combined with advanced bioinformatics is beginning to show its power in delineating disease entities that are otherwise indistinguishable. This refinement in tumor classification allows a more accurate prediction of outcome of disease for patients that present with the same stage of disease based on conventional clinical and histopathological criteria. Gene activities determining the biological behaviour of the tumor may indeed be more likely to reflect the aggressiveness of the tumor than general parameters such as tumor size, age of the patient, or even tumor grade. The immediate clinical consequences are therefore that treatment schemes can be tailored based on the gene activity patterns of the primary tumor. Using gene expression profiling with cDNA microarrays, Perou and colleagues showed that there are several subgroups of breast cancer patients based on unsupervised cluster analysis: those of 'basal type' and those of 'luminal type'. These subgroups differ with respect to outcome of disease in patients with locally advanced breast cancer. In addition, microarray analysis has been used to identify diagnostic categories (e.g. BRCA1 and BRCA2, estrogen receptor status). We used gene expression profiling with DNA microarrays harboring 25,000 genes on 78 primary breast cancers of young lymph-node-negative patients to establish a signature, predictive for a short interval to distant metastases. This 'poor prognosis' signature consists of genes involved in the cell cycle, invasion and angiogenesis. The prognosis signature is superior to currently available clinical and histopathological prognostic factors in predicting a short interval to distant metastases (odds ratio = 18 [95% confidence interval = 3.3-94], P < 0.001, multivariate analysis). We have validated our findings of this poor prognosis profile on a large unselected consecutive series of LN0 as well as lymph-node-positive (LN+) young breast cancer patients (n = 295). The analyses confirm that the profile is a strong independent factor in predicting outcome of disease for LN0 patients in general (10-year overall survival for the good prognosis profile 96% vs 50% for the poor prognosis profile). Furthermore, the profile is also powerful for LN+ patients. At present, the prognostic significance of the 70 genes is tested in older breast cancer patients. Nowadays, consensus guidelines in the management of breast cancer select up to 95% of lymph-node-negative young breast cancer patients for adjuvant systemic therapy (e.g. NIH and St Gallen consensus criteria). As 70–80% of these patients would have remained disease-free without this adjuvant treatment, these patients are 'overtreated'. The 'poor prognosis' signature provides a novel strategy to accurately select patients who would benefit from adjuvant systemic therapy and can greatly reduce the number of patients that receive unnecessary treatment. Our data revealed that already small tumors display the metastatic signature, and recent results show that the molecular program established in a primary breast carcinoma is highly preserved in its distant metastasis. These findings suggest that metastatic capability in breast cancer is an inherent feature, and is not based on clonal selections. The results further imply that neo-adjuvant treatment given to patients based on (yet to be established) response expression profiles of their primary breast tumor might indeed prevent the outgrowth of micrometastases. Currently, the EORTC breast group is preparing a 5000-patient randomized trial to compare the efficacy of guidance of breast cancer patients for adjuvant chemotherapy based on either 'conventional' St Gallen consensus criteria or the microarray prognosis test (MINDACT trial within the EU-TRANSBIG program). The aim of the study is to confirm that the microarray test will save up to 30% of the patients from unnecessary chemotherapy and to identify 5% of them who are nowadays 'undertreated'.