Molecular markers in breast cancer: no longer a ‘free’ run from laboratory to the clinic

Abstract

Biomarkers in MedicineVol. 2, No. 6 EditorialFree AccessMolecular markers in breast cancer: no longer a ‘free’ run from laboratory to the clinicAndrea NicoliniAndrea NicoliniUniversity of Pisa, Department of Internal Medicine, via Roma 67, Pisa 56126, Italy. Search for more papers by this authorEmail the corresponding author at a.nicolini@int.med.unipi.itPublished Online:12 Dec 2008https://doi.org/10.2217/17520363.2.6.531AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit In Western countries, breast cancer remains the most common cancer and the main reason for cancer-related death in women between 35 and 55 years of age [1,2]. Thus, any advance in the field has a great social impact and is rapidly acquired by the scientific community and clinical oncologists.In the last few decades, the identification of new molecular markers for prognostic as well as diagnostic, predictive and therapeutic purposes has been one of the basic research fields most developed to improve the management of breast cancer patients.Conventional clinicopathological factors for the prognosis of breast cancerBefore the 1950s, only few clinicopathological factors, namely tumor size (cm), node status (positive or negative), grade (grade of differentiation) and evidence of metastatic disease, were used to establish the prognosis of breast cancer patients.Around the 1950s, the International Union Against Cancer (UICC) worked on a project to provide a graphical representation of the anatomical extension of any malignant neoplasm. All the aforementioned clinicopathological factors except for grade were necessary to define a pathological (p) tumor (T), nodes (N) and metastatic involvement (M) based on classification known as pTNM that was considered the only classification appropriate for prognostic purposes and to allow treatment after the removal of primary cancer. The first version of pTNM by UICC was published in 1968. In 1987, the TNM classification of the UICC and that of The American Joint Committee on Cancer (AJCC) joined with the fourth version. Thereafter, pTNM classification was continuously updated up until 2002, when the sixth version was published. In the latest versions, grading and receptor status were also recommended to be considered. Therefore, from the mid-1900s onwards, pTNM and the consequential division by stages were the only classifications widely used to define prognosis of breast cancer patients.New emerging molecular markersThe enormous and rapidly increasing progress of techniques in molecular biology and genetics has permitted basic research to elucidate many molecular pathways involved in tumor growth, invasion and metastasization. Epigenetic changes, such as DNA methylation, have also been shown for several genes involved in cell cycle control, apoptosis, angiogenesis and detoxification processes [3–5]. Therefore, a great number of molecular markers related to specific functions and providing insights into cellular mechanisms, including oncogene or oncosuppressor gene deregulation, neoangiogenesis, cell cycle regulation, adhesion, invasion or extracellular matrix modification became available [6].Others are related to the damage provoked by the tumor in different organs or the immune response of the host to molecules overexpressed or overexposed by the tumor [7–9]. Among these molecular markers, estrogen and progesterone receptors have been proven and widely used. Since its introduction into clinical practice, this measurement was considered to provide additional information for prognosis and to predict probable hormone-responsiveness or not of cancer cells.As well as estrogen and progesterone receptors, a long list of putative molecular markers have been proposed. Among prognostic markers, EGF receptor (EGFR), HER2/neu gene (c-erbB2), HER2 protein (p185) (approximately a third of breast cancers do not express estrogen receptor [ER] and are regulated by growth-factor pathways using other receptors), MIB-1 (i.e., antibodies recognizing antigens related to cell cycle proteins) and p53 (p53-suppressive gene encodes for a 53-KDa nuclear phosphoprotein, wild-type p53, involved in controlling cell cycle regulation, cell differentiation and the surveillance of genomic integrity) are those that have been documented the most [10]. In addition, HER/neu gene overexpression has been shown to select hormone-resistant breast cancers and those that are candidates for immunotherapy with anti-HER2 protein monoclonal antibodies (Herceptin®). In addition, other clinicopathological factors such as microvessel count, bone marrow micrometastatic disease, circulating tumor cells and newer approaches such as the number of dividing cells (the mitotic index) and the percentage of cells in the tumor that are making new DNA, (i.e., S-phase fraction) have been investigated and proposed by different researchers for prognostic purposes [10]. In recent years, microarray technology, with its ability to simultaneously examine thousands of genes, permitted visual recognition of tumors that share the so-called ‘genetic signature’ [11]. Using this technology, breast tumors have been grouped into six categories, defined as basal-like, erbB2-positive, normal breast-like and luminal types A, B and C, with luminal types sharing the expression of ER and ER-related genes, and basal-like and erbB2-positive subtypes associated with the shortest survival times [12].Among risk-assessment markers, the BRCA1 and BRCA2 genes have been found to be associated with familial breast cancer [13], while high concentrations of prolactin, insulin, IGF-1 and androgens (i.e., testosterone and adrenal androgens) have often been detected in subjects who eventually developed breast cancer [14]. Other markers that are detected in serum, such as carcinoembryonic (CEA) and mucine-like antigens, are commonly considered tumor burden-related markers [15]. They have largely been investigated for early detection and monitoring of response to treatment by metastatic disease [16,17]. Further markers of response or progression of metastatic disease during treatment can be expected once a better understanding of the relationship between the breast cancer microenvironment and cell-mediated immunity of the host is achieved [18–20].Presently, a large number of molecular markers and many clinicopathological factors can be assessed. Moreover, this long list is inevitably destined to increase. Theoretically, most of them have the potential to refine the prognosis, while others, such as the BRCA1 and BRCA2 genes or tumor burden-related circulating markers, are indicated for risk assessment or postoperative monitoring. Nevertheless, in spite of this large availability, these two related questions have arisen: ▪ Among the available markers, which of them are actually useful?▪ Among the useful markers, which ones have a favorable cost–effectiveness ratio?In fact, the principal aim of any marker is to drive the decision-making process of the clinical oncologist, which has a relevant impact on healthcare expenses.Business, regulation & clinical utilityA long time has passed since estrogen and progesterone receptor determination entered into standard clinical practice. Thereafter, many others have been investigated and proposed. They initially evolved as single molecular elements and progressed to reflect insights into pathophysiology as a panel of genes and their associated mutations, the so-called ‘genetic profiling’ or ‘signature’, up to the recent possibility of assessing the entire transcriptome or proteome to distinguish diseased from normal tissues or disease categories with different risk profiles. In spite of these enormous advances and concomitant financial investments in the field, the only other molecular marker that has thus entered into clinical guidelines is HER2/neu gene expression. In fact, in 2005, the International Expert Consensus on the Primary Therapy of Early Breast Cancer considered this single molecular marker relevant for defining endocrine responsiveness and risk categories [21]. It should be inferred that the remaining molecular markers are either not useful or insufficient documentation is available. BRCA1 and BRCA2 testing is recommended in selected populations of subjects with high incidence of familial breast cancer, while circulating CEA and CA15.3 can be useful for postoperative monitoring in the first years following removal of primary breast cancer in patients with a high risk of relapse. However, in view of increasing demands by clinical oncologists for a more refined prognosis and management of breast cancer patients with respect to the so-called targeted and/or tailored therapies, it must be recognized that there is a significant lack of regulations by independent authorities.In 1996, a Tumor Marker Grading Utility System to standardize tumor-marker information for clinical utility and to establish an investigational agenda for evolution of new tumor markers was proposed [22]. Following this, improved patient outcomes, and more cost-efficient investigation and application of tumor markers were expected. So far, this program has often not been applied, and efforts to standardize the use of tumor markers in clinical studies have only been considered as anecdotal. It is likely that failure to provide definitive validation, qualification and comparison among markers of the same category has been the main obstacle impeding their integration into current clinical practice and patient management. In 2003, a working group developed a check-list and flow diagram to improve the quality and completedness of studies reporting on diagnostic accuracy [23]. The validation of the Standard for Reporting of Diagnostic Accuracy (STARD) initiative is expected to contribute to a constant improvement in the quality of study designs, including those on cancer markers. More recently, the Pharmaceutical Research and Manufacturers of America and the US FDA created a consortium for the development of biomarkers established under the Foundation for NIH in collaboration with the Centers for Medicare and Medicaid Services, academic institutions and representatives from the private sector, including pharmaceutical, biotechnology and diagnostic companies [24]. This consortium is open to public or private institutions, and will manage biomarker programs to ensure scientific integrity, appropriate resources and compliance with relevant statutes. There is the hope that these are the first steps of a necessary and constant collaboration among academia, industry and regulatory agencies. To optimize biomarker application, it is likely that relational databases of many long-term followed-up patients are required to compare patient molecular profiles to clinicopathological characteristics. 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