Laboratory-Clinic Interface
Molecular and protein markers for clinical decision making in breast cancer: Today and tomorrow

https://doi.org/10.1016/j.ctrv.2013.09.014Get rights and content

Abstract

In early breast cancer (eBC), established clinicopathological factors are not sufficient for clinical decision making particularly regarding adjuvant chemotherapy since substantial over- or undertreatment may occur. Thus, novel protein- and molecular markers have been put forward as decision aids. Since these potential prognosis and/or predictive tests differ substantially regarding their methodology, analytical and clinical validation, this review attempts to summarize the essential facts for clinicians. This review focuses on those markers which are the most advanced so far in their development towards routine clinical application, i.e. two protein markers (i.e. uPA/PAI-1 and IHC4) and six molecular multigene tests (i.e. Mammaprint®, Oncotype DX®, PAM50, Endopredict®, the 97-gene genomic grade, and 76 gene Rotterdam signatures). Next to methodological aspects, we summarized the clinical evidences, in particular the main prospective clinical trials which have already been fully recruited (i.e. MINDACT, TAILORx, WSG PLAN B) or are still ongoing (i.e. RxPONDER/SWOG S1007, WSG-ADAPT). Last but not least, this review points out the key elements for clinicians to select one test among the wide panel of proposed assays, for a specific population of patients in term of level of evidence, analytical and clinical validity as well as cost effectiveness.

Introduction

Breast cancer (BC) is one of the leading malignancies and causes of cancer death for women [1], [2]. The significant survival improvement compared to the 1990’s correlates with early diagnosis and adjuvant therapy improvement. A major step has been to define BC diversity and to accurately categorize patient subpopulations [3], [4]. Genomic information can be combined with clinicopathological characteristics to estimate recurrence risk (prognostic value) and predict therapy efficacy (predictive value). Identifying high-risk patients for recurrence and administering optimal therapies but avoiding overtreatment are major issues in BC management as therapy resistance and metastasis processes need to be effectively targeted for improvement of survival [5].

Current BC classification and assessment remain strongly based on clinicopathological criteria, including patient age, tumor size, lymph node invasion, histological type, and grade [6]. Histological characterization is still evolving, driven by development of targeted therapies, including endocrine and anti-HER2 therapies, and by proliferation index evaluation. Routine immunohistochemistry (IHC) is performed for estrogen (ER) and progesterone receptor (PR), HER2 overexpression, and recently Ki67.

Besides individual mutation analysis, gene expression microarrays have allowed researchers to perform simultaneous expression analyses of thousands of genes in a single experiment to create molecular tumor profiles. In 2000, Perou and colleagues published the first paper classifying BC into intrinsic subtypes based on gene expression profiling [7], [8]. Progressively, new classifications have emerged defining now 6 subtypes: luminal A, luminal B, HER2-enriched, basal-like, normal breast-like, and more recently, the claudin-low or mesenchymal-like subtype [9], [10]. Although the classically called triple negative tumors are mainly represented among the basal-like subtype, they do not always belong to this subtype and inversely, this subtype does not contain only triple negative tumors [11], [12]. Recently, Lehmann and colleagues suggested to further molecularly subdivide triple negative BC into six subtypes (2 basal-like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like, and a luminal androgen receptor subtype). The authors even showed potential therapeutic consequences. Yet, at the moment, these subtypes have not been validated for clinical routine use [13]. These new intrinsic classifications are in permanent evolution with more possible subtypes in the near future [4], [13], [14].

Nonetheless, introduction of molecular subtypes opened new ways for clinicians to classify, diagnose and treat BC [9], [14], [15]. Moreover, new signaling pathway identification for each subtype has proven to be useful for drug discovery and for identification of new molecular markers [3].

At primary diagnosis, approximately 60% of patients with invasive BC are node-negative, with 94% of these expected to have no distant metastasis at ten years if treated by locoregional and adjuvant systemic therapy (www.tumoRregister-muenchen.de). Without adjuvant systemic therapy, the risk of relapse among node-negative patients is considerably higher [16]. About 80% of these patients, i.e. those who have ER/PR positive disease, will receive adjuvant endocrine therapy. For patients with HER2-positive disease (about 15%), additional chemotherapy and targeted therapy are recommended. The HER2-negative, hormone receptor positive population can be intrinsically divided in subpopulations with low, average and high risks of recurrence. Adjuvant therapy, either endocrine or chemotherapy followed by endocrine therapy, should be decided accordingly. Yet risk stratification based on only clinic-pathological parameters may be misleading and cause under- or overtreatment. Since 2007, international guidelines (e.g., St. Gallen, ASCO, AGO) have recommended to additionally use validated protein or gene expression tests reflecting the intrinsic tumor characteristics to improve the clinical risk stratification [17], [18].

Section snippets

Prognostic and predictive tests for early breast cancer

The main goal in development of prognostic and predictive markers is to develop quality assured (QA) certified tests that can be routinely used, at acceptable cost for all patients [19]. Moreover, clinicians should easily be able to determine which test is suitable for each individual patient. Ultimately, clinicians will combine new and established markers to:

  • -

    optimize cancer diagnosis

  • -

    orientate therapy choice

  • -

    support patient follow-up.

To reach these goals, thorough marker development according to

Comparisons of several prognostic tests in early breast cancer

We focused this review on the 2 protein and 6 molecular assays we considered the most advanced regarding evaluation of their clinical utility. The major role of these markers is the treatment decision making regarding adjuvant therapy. Thus, we did not emphasize recent hypothesis-generating data related to the impact of the signatures in the neoadjuvant therapies. Nonetheless, other protein markers and signatures are already quite advanced in their development, even marketed, based on

MINDACT trial

The prospective validation of the Mammaprint® assay, as a prognostic tool to improve risk assessment and treatment decision making for eBC, is ongoing with the MINDACT trial. The TRANSBIG consortium launched this prospective, phase III randomized, multicentric clinical trial, called MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) in 2006. The Mammaprint® assay is assessed in parallel with the more conventional Adjuvant! Online tool for assigning adjuvant chemotherapy to

Decision impact studies

Prospective observational decision support studies have been performed worldwide for several of the multigene assays. Using Oncotype DX® (n = 379), treatment decisions changed in about a third of patients with 33% fewer patients actually receiving chemotherapy than originally planned. Patients’ decisional conflict score improved and physicians’ confidence increased [98]. From a healthcare payer perspective, costs were lower by about 561€ for Oncotype DX® vs. standard of care [99]. Also for

Discussion

The need to avoid over- and undertreatment in the curative adjuvant setting has motivated the search for efficient prognostic and predictive markers in eBC over the last two decades. Of the numerous tests evaluated at the moment, only very few are so far suitable for clinical use because of their technical and clinical validity. The possibility to combine determination of already validated protein markers to clinicopathological criteria also appears as a safe strategy to use.

The need for tumor

Conclusion

Protein and molecular tests to answer specific clinical questions are still relatively new and have introduced substantial challenges for clinicians. In particular, their clinical validity, technical reproducibility, and reliability which are prerequisites for diagnostic and/or predictive assays in patient management need to be addressed quickly. Technical ease and price will be crucial to consider before general implementation of these tests in the clinic. All such tests evaluated in

Conflict of interest statement

NH has received honoraria for lectures from Genomic Health and obtained research funding grant from Genomic Health and NanoString. KS has received honoraria for lectures from NanoString. The other authors declare that they have no conflict of interest relating to the publication of this manuscript.

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