Elsevier

Surgical Oncology

Volume 18, Issue 4, December 2009, Pages 366-378
Surgical Oncology

Review
Gene expression profiling: Decoding breast cancer

https://doi.org/10.1016/j.suronc.2009.07.005Get rights and content

Abstract

Gene expression assays that are used in daily clinical practice for treating early breast cancer patients have been introduced in the clinic only recently. This review discusses the development of these arrays, summarizes the validation of those that are commercially available and indicates how the information provided by these assays can help in the care of patients. The review also provides an extensive overview of commercially available assays focusing on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA.

Introduction

Measuring the expression of thousands of genes at the same time using microarrays has answered many questions that have been impossible to answer previously. A recent Pubmed search for “microarrays” generated over 28,000 items, indicating its widespread use. It was anticipated that this technique would quickly find its way into clinical diagnostics, however, only a few are currently in clinical use. As gene expression profiling represents a major change in how we make clinical decisions, it is understandable that clinical adaptation has been slow.

Tumor metastasis is a complex biological process that involves many steps starting at the tumor site and ending at the secondary tumor site. These processes involve biological pathways that are important in tumor formation and metastasis as depicted in Figure 1. There are many intersections on this roadmap along with many side roads and also many one-way streets from which there is no point of return. Thus, the ability of a tumor to survive and metastasize is determined by the molecular roadmap that it is committed to follow.

In breast cancer, the metastasis risk can be predicted by the overall gene expression of the primary tumor. This finding challenged the idea that the metastatic potential is acquired relatively late during the multi step process of tumor formation [1]. However, molecular signatures are preserved throughout the life of the tumor, even after the tumor has metastasized indicating that the original signature is the tumor's blueprint [2], [3].

The concept of individual molecular signatures can be illustrated by the fact that the approximately 400 different cell types in the body each have different gene expression profiles. These profiles reflect their distinct cellular functions even though they all belong to one individual. Of importance, profiles have been shown to retain part of their gene expression patterns in the metastatic setting and these profiles can be used to determine the primary tissue of origin. Thus, the genomic signatures of metastatic cancers of unknown primary can be used to help characterize their respective primary sites of origin. In addition, it has been shown that poorly differentiated and undifferentiated tumors of a given cancer type retain expression patterns observed in their particular well-differentiated tumors [4], [5].

In the past decade, efforts have been directed at determining gene expression profiles for diagnosis, prognosis and prediction. Whole genome microarrays have become readily available and have enabled characterization of profiles for use in the clinical oncology setting.

The natural history of breast cancer is changing as the benefits of screening mammography and adjuvant chemotherapy are becoming evident with earlier diagnosis of smaller tumors without lymph node involvement. Thus, the need for better stratification of patients is becoming increasingly important in order to identify those patients who will not need to be treated with adjuvant chemotherapy after optimal locoregional treatment, as well as identifying those high-risk patients who will benefit from certain chemotherapy regimens (Figure 2).

Unbiased profile development

Profiles for predicting tumor recurrence can be developed by comparing whole genome expression profiles of tumors that either metastasize or that do not recur. Those genes that are significantly different between the two tumor groups are probably the ones that can discriminate good and poor prognosis patients. The genes have been extracted in an unbiased way; there have been no human assumptions as to why certain genes end up in the profile. The next phase of a gene expression profile development is to validate whether the developed profile can be used in patient populations other that the patients the profile was developed in. It is the independent validation studies that determine the strength of a diagnostic profile.

Section snippets

Genetic profiles

MammaPrint is a genetic profile for breast cancer prognosis and prediction, developed in 2001 at the Netherlands Cancer Institute (NKI) in Amsterdam to help clinicians decide how to treat a growing population of patients with early stage breast cancer [6]. Researchers set out to develop a genetic signature that could correctly distinguish patients with a high risk of developing metastases from those who could be safely be spared adjuvant chemotherapy treatment as their long term distant

How genetic information can enable a personalized approach

After optimal locoregional treatment, which may include a variety of therapeutic modalities such as breast conserving surgery, mastectomy with or without immediate reconstruction and sentinel node sampling with nodal dissection if metastases are encountered, the patient is a candidate for adjuvant therapy. Ideally one would like to forego adjuvant chemotherapy in those patients who are likely to be cured by the locoregional treatment alone. Gene expression profiling enables the clinician to

Storing RNA

To enable the development of representative response profiles, the genomic information from which these profiles are developed needs to be properly preserved in a non-contaminated, non-degraded fashion. In this regard, proper fresh tissue banking has become important not only in the clinical research setting, but also for routine daily clinical practice. Information contained in the RNA of the tumor cells is degraded when the tissue is processed and embedded in paraffin, the most common

Current risk stratification of breast cancer patients

Many tumor characteristics affect the outcome of patients and many different classification systems have been devised for classifying patients according to clinico-pathologic criteria. The clinical guidance of these classification systems in the HER2 negative, early stage breast cancer patients according to NCCN, St Gallen and other consensus guidelines differ significantly and the clinical guidance offered for patients differs according to guidelines being used.

MammaPrint validation studies

MammaPrint was developed and initially validated in a series of 295 consecutive (i.e. to ensure no selection bias) women with breast cancer collected according to an NKI protocol [18]. The patients were all part of the tumor bank at the Netherlands Cancer Institute (NKI) which included all patients seen for any cancer diagnosis and from which all patients with a breast cancer diagnosis who were untreated and stages 1–3 were included. This tumor bank dates from 1986 when the NKI was founded and

From prognosis to response

The rationale for the development of gene expression profiles for prognosis and chemotherapy response prediction lies in the hypothesis that the natural history of a tumor is determined by its underlying regulatory gene pathways. By comparing genome wide expression data from patients who have developed metastases (poor prognosis) with patients who remained metastasis free (good prognosis), those genes that are associated with the development of metastases will emerge. A profile that can

Conclusion

The goal of any prognostic and/or predictive assay is to augment the clinician's ability to make meaningful treatment decisions that influence patient outcomes. This level of evidence generally requires completion of a prospective trial wherein the result of the test in question is the critical variable being examined. Such a trial is MINDACT, the multi-institution EU study designed to determine if patients are better served by having their therapy prescribed by MammaPrint or by Adjuvant!

Acknowledgement

The authors would like to thank Guido Brink for providing input on Table 1.

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