Advances in Clinical Chemistry, Volume 71, is the latest installment in this internationally acclaimed series. This latest volume contains chapters authored by world-renowned clinical laboratory scientists, physicians, and research scientists. The serial discusses the latest and most up-to-date technologies related to the field of clinical chemistry and is the benchmark for novel analytical approaches in the clinical laboratory.
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Biomarkers in Breast Cancer
Where Are We and Where Are We Going?
Michael J. Duffy*,┼,1; Siun Walsh*; Enda W. McDermott*; John Crown╬ * UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland
┼ UCD Clinical Research Centre, St. Vincent's University Hospital, Dublin, Ireland
╬ Department of Medical Oncology, St. Vincent's University Hospital, Dublin, Ireland
1 Corresponding author: email address: firstname.lastname@example.org
Biomarkers play an important role in the detection and management of patients with breast cancer. Thus, BRCA1/2 mutation testing is used for risk assessment in families with a high prevalence of breast and ovarian cancer. Following a diagnosis of breast cancer, measurement of multi-analyte profiles such as uPA/PAI-1 or Oncotype DX may be used for determining prognosis and identifying lymph node-negative patients who may be spared from having to receive adjuvant chemotherapy. Other -gene tests such as the PAM50 ROR, Breast Cancer Index, and EndoPredict have been reported to predict the development of late recurrences and thus may be of value in selecting patients for extended hormone therapy. Mandatory assays include estrogen receptors for identification of endocrine-sensitive cancers and HER2 in selecting patients for treatment with anti-HER2 therapy (e.g., trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine). Finally, serum biomarkers such as CA 15-3 or CEA may be used in monitoring therapy in patients with advanced disease receiving systemic therapy. Promising new biomarkers undergoing evaluation include circulating tumor cells and circulating tumor-derived DNA.
1 Use of Biomarkers in the Identification of Women at Increased Risk of Developing Breast Cancer (Risk Assessment)
Biomarkers are playing an increasingly important role in the detection and management of patients with several different cancer types, including breast cancer [1,2]. For breast cancer, biomarkers are particularly useful in the identification of individuals at increased risk of developing the malignancy within high-risk families, determining prognosis at the time of initial diagnosis, identifying the most appropriate systemic therapy, postoperative surveillance, and monitoring therapy in advanced disease. The aim of this chapter is to critically review the role of biomarkers in these different settings. In addition, we will review new biomarkers emerging for breast cancer and speculate on their likely integration into routine use.
It has been known for decades that certain families have an increased risk of breast cancer. Although defects in several different genes are known to predispose to breast cancer, the best characterized are BRCA1 and BRCA2 . Both BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of breaks in double-stranded DNA. These genes thus play a critical role in maintaining integrity of DNA. Although both genes are involved in DNA repair, their roles are distinct and nonoverlapping.
In a large prospective study, the cumulative risk of developing breast cancer by age 70 years was 60% for BRCA1 carriers and 55% for BRCA2 carriers . In the same study, the corresponding risks for the development of ovarian cancer were 59% and 16.5% for BRCA1 and BRCA2 carriers, respectively. Interindividual variation in risk is thought to be due to the location and type of mutation as well as environmental factors. Pathogenic mutations in BRCA2 but apparently not in BRCA1 can also increase susceptibility to pancreatic and prostate cancers .
BRCA1/2 germline testing is thus now a common practice for risk assessment in families with a high prevalence of breast or ovarian cancer. According to the U.S. Preventive Services Task Force (USPSTF) guidelines , primary care providers should "screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2)." It was furthermore recommended that those with positive findings should undergo genetic counseling. BRCA genetic testing was not recommended for women without a family history of the disease.
Potential benefits of undergoing germline BRCA testing for inherited breast cancer susceptibility include a more accurate risk assessment for the individual as well as their family, with the possibility of early cancer detection or indeed prevention. Individuals found to be mutation carriers should be advised to consider the options both for decreasing the risk of breast cancer and for early detection. These include regular surveillance with mammography and magnetic resonance imaging (MRI), prophylactic bilateral mastectomy, oophorectomy, or administration of prophylactic tamoxifen or prophylactic raloxifene [6,7]. Currently, the USPSTF recommends administration of prophylactic tamoxifen or prophylactic raloxifene to women at high risk of breast cancer and have a low risk of suffering from adverse medication effects .
Although BRCA1 and BRCA2 are the best characterized and the most prevalent breast cancer susceptibility genes, pathogenic mutation in these genes is believed to be responsible for only approximately 15-25% of breast cancers with a hereditary component . Other genes implicated in conferring an increased susceptibility to breast cancer are listed in Table 1. As inherited defects in these non-BRCA genes appear to be rare, routine genetic testing for them is not widely carried out at present. However, in the near future, it is likely that testing for breast cancer genetic susceptibility will involve panels of genes or whole-exome sequencing, rather than investigating individual genes such as BRCA1 or BRCA2. The advantage of multi-gene testing is that for some individuals it may save time and reduce costs compared to sequential testing of one or a small number of genes. Interpretation of results from gene panel, however, is presently complicated due to lack of data on penetrance of the different mutations and the increased likelihood of finding alteration of unknown clinical significance. Furthermore, guidelines for the management of subjects found to harbor many of these alterations are not presently available .
Breast Cancer Susceptibility Genes and Their Penetrance
Gene Penetrance BRCA1/2
High TP53 (p53)
2 Use of Biomarkers in Determining Prognosis
Following a diagnosis of primary invasive breast cancer, the most urgent questions to be addressed are: what is the prognosis and should adjuvant systemic therapy (e.g., chemotherapy) be administered? Thus, the accurate determination of prognosis at the time of diagnosis of breast cancer is clearly essential for optimum patient management, especially to avoid overtreatment of nonaggressive disease and undertreatment of aggressive forms. Traditionally, pathological and clinical criteria such as tumor size, tumor grade, number of lymph nodes with metastasis, patient age, and patient morbidity status were used for this purpose. Of these factors, the number of lymph nodes with metastasis has been the most widely employed. However, with the advent of screening mammography in recent years, more than 50% of women diagnosed with breast cancer present with lymph node-negative disease. Furthermore, most of these women are cured of their breast cancer using surgery and radiotherapy and are therefore unlikely to benefit from adjuvant chemotherapy. Despite this high cure rate with local treatment, most lymph node-negative patients currently receive adjuvant chemotherapy. Thus, currently, the main requirement for prognostic biomarkers in breast cancer is to aid the differentiation of newly diagnosed lymph node-negative patients who are cured by surgery and radiotherapy from those women who might benefit from adjuvant chemotherapy.
Over the last 20 years, an enormous amount of work has been carried out to address this issue and hundreds of putative biomarkers have been proposed for predicting outcome in women with newly diagnosed breast cancer . Most of these studies, however, were of low evidence  due to inadequate design, low numbers of patients, failure to show independent prognostic value, inappropriate clinical validation and failure to demonstrate clinical utility . Among the most widely investigated are the tumor tissue biomarkers, urokinase plasminogen activator (uPA)/PAI-1, gene-expression profiles (e.g., Oncotype DX, MammaPrint), Ki-67, and the serum biomarkers, CA 15-3 and CEA [2,9].
2.1 uPA and PAI-1