Therefore, a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand, and costs and side effects on the other. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer.
This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors ICMJE criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author s and source are given appropriate credit.
The genetic diagnosis of hereditary cancer became possible by the identification of germ-line mutations in. This chapter discusses molecular diagnostics in the evaluation of cancer. Cancer is a genetic disease of somatic cells. Molecular technologies are being.
Adjuvant systemic treatment of breast cancer is moving away from the limited portfolio of traditional hormonal drugs and chemotherapy, towards a gamma of novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules. All these therapeutic approaches are unfortunately effective in a limited number of patients and are often associated with high costs and significant side effects.
Over recent years, progress in molecular techniques has made it possible to analyse formalin fixed paraffin embedded FFPE tumour material of larger cohorts of patients. Copy number analysis by array comparative genomic hybridisation CGH showed frequently occurring gains of 3q, 7p, 8q 10p, 12p, 16p and 17q, and loss of 2q, 3p, 4p, 4q, 5q, 12q, 16p and 18q in BRCA1 germline mutation related cancers. BRCA2 related breast cancers show more frequently gains of 8q, 17q22—q24 and 20q13, and loss of 8p, 6q, 11q and 13q compared to BRCA1 related cancers. These different classes have varying clinical behaviour and have led to a new way of thinking about classification of breast cancer going beyond morphology.
Nevertheless, good correlations exist between these intrinsic subtypes and morphology. The basal-like group contains high grade ductal medullary and metaplastic cancers as well as the low grade salivary gland type cancers adenoid cystic cancers [AdCC], acinic cell cancers, myoepithelial cancers. The luminal A group contains mainly low grade ductal, lobular, ductulolobular, tubular, cribriform, mucinous and micropapillary cancers. Besides, these tests are not available for local testing in pathology labs, are time consuming and expensive.
Therefore, a more practical approach is probably to use an immunohistochemical surrogate as depicted in Table 1. PAM50 and Blueprint are two commercially available gene expression test for intrinsic subtyping from centrally at Nanostring and Agendia, respectively. Translocations Adenoid cystic carcinoma While being a frequent cancer type in the minor and major salivary glands with frequent perineural invasion and poor prognosis, AdCC is a rare cancer type in the breast, accounting for 0. Secretory cancer Secretory cancer is a rare breast cancer type that occurs at all ages, even at quite young age.
Recently, it was shown that secretory cancer is characterised by a balanced chromosomal translocation t 12;15 p13;q25 , which leads to the formation of an oncogenic ETV6-NTRK3 fusion gene encoding a chimeric tyrosine kinase, also demonstrated in paediatric mesenchymal cancers. Prognostic markers Gene expression tests Several gene expression tests have been developed to predict prognosis and response to therapy.
The above described PAM50 has proven prognostic value. It can be applied on FFPE and has been validated for local application in pathology labs, and is available from Sividon Diagnostics. It was proven to be prognostically important in several studies level I-II evidence , especially in combination with lymph node status and tumour size, 13 and gives a binary prognostic indication.
It was originally developed as a prognostic factor with evidence level I on frozen material but was recently also validated on FFPE material. It is available only centrally from Genomic Health and gives a three-tiered prognostic indication. These gene expression tests in general provide good prognostic information and are analytically well validated except. A recent paper indicated that these tests may be significantly suffer from intra-tumour heterogeneity. The added prognostic value to type and grade is likely limited, 17 but their better reproducibility are arguments in favour. No prognostic comparative studies have been performed, so decisions on the preferred test are usually taken based on local arguments.
Predictive markers Gene expression tests The value of the above described gene expression tests EndoPredict, MammaPrint and Oncotype Dx lies in their predictive value rather than their prognostic power in view of their high costs. If patients that are deemed eligible for chemotherapy based on classic prognostic factors can be safely spared chemotherapy when their gene expression test turns out to be favourable, much money can be spared elsewhere and application may be cost-effective.
All these tests have proven to have such predictive value at level I evidence, although lack of intra-tumour heterogeneity studies remains a weak point. Further, comparative predictive studies have been performed, so decisions on the preferred gene expression test are usually taken based on local preferences rather than firm scientific data.
ESR1 mutations leads to conformation change which mimics activated ligand-bound receptor and induces ligand-independent ER activity, 22 resulting in tumour growth despite endocrine therapy. The mutants appear to retain some sensitivity to drugs directly targeting the receptor suggesting potential pharmacologic strategies for these patients. Although ESR1 mutations are very uncommon in primary breast tumours, 24 metastases more frequently harbour mutations in the ligandbinding domain resulting in endocrine resistance.
Aromatase inhibitor treatment in the metastatic setting rather than in the adjuvant setting induces ESR1 mutations. On examestane, however, ESR1 mutations do seem to indicate worse prognosis. Overall, ESR1 mutations seem to be associated with more aggressive disease biology.
The use of demethylating agents was shown to reactivate ER expression which reveals a potential new strategy to overcome endocrine resistance in breast cancer patients. However, it not a very practical primary screening tool for HER2 copy number status since it is time consuming, signals fades over time, tumour morphology is more difficult to appreciate and tumour heterogeneity can easily be missed.
MLPA can analyse up to 45 genes in one assay, and is thus able to simultaneously test different genes that are important for therapy selection or prognosis. All these techniques show an overall good correlation with each other in comparative studies, but not without discrepancies both ways. A clinical diagnostic test for HER2 should accurately determine HER2 protein levels or gene copy number and should be reproducible and precise across multiple sites and users. Decisions on how to test can therefore be taken locally after proper local validation.
Correction with CEP17 probes may thereby provide misleading HER2 gene status assessment results, and the absolute copy number of HER2 likely serves best to indicate eligibility for trastuzumab therapy. Therefore, the market concentration is high and there is not much variation in the level of competition. South Korea is currently entirely dependent on imports for blood cancer diagnostic kits and is experiencing high technological barriers to entry [ 3 , 4 , 5 ].
Molecular diagnostics has demonstrated the highest diagnostic accuracy within the field of in vitro diagnostics and for this reason, its market is expected to have the highest growth compared to other in vitro diagnostic markets. Strong growth is anticipated in Korea, China and India, where the markets are in the growth stage, due to the increasing demand for clinical testing and analysis.
Market size of the global cancer diagnosis by technology platform presents in Table 1. Within the field of blood cancer molecular diagnostics, the technology exhibiting the highest rate of growth is NGS [ 7 ]. The market for early diagnoses and cancer molecular diagnostics kits are forecasted to grow due to factors including the increased incidence of cancer, growth of biomarker market and development of molecular technology.
Based on the data on the global market for molecular diagnostics of blood cancer, we performed a forecast of the platform-based cancer diagnosis market from , by applying a growth rate of Forecasts for the global market for blood cancer molecular diagnostics kits [ 8 ]. Size of the domestic molecular diagnostics market [ 9 ]. The most common type of cancer in was thyroid cancer, followed in ranking by stomach cancer, colon cancer, lung cancer, breast cancer, liver cancer, and prostate cancer.
According to the Korea Central Cancer Registry published in , there were , cancer cases in South Korea in , among these, the most frequently occurring type was thyroid cancer, followed by stomach cancer, colon cancer, lung cancer, breast cancer, liver cancer, and prostate cancer in order of frequency [ 10 ].
Within the category of blood cancer, there were cases of Non-Hodgkin lymphoma, cases of myeloid leukemia, cases of multiple myeloma, cases of lymphocytic leukemia, cases of pediatric lymphoma, cases of pediatric leukemia, and cases of malignant lymphoma. Within the total cancer incidence, the number of blood cancers accounted for 6. As with other types of cancers, the higher the age group, the higher the prevalence of blood cancer.
Analysis shows that recently, the incidence of cancer patients has steadily increased due to environmental problems and changes in eating habits which is also why molecular diagnostics technology for monitoring cancer treatment and performing prognoses is becoming more and more the important.
Unfortunately, there is no objectively reliable data regarding the South Korean market for blood cancer molecular diagnostics, and therefore our estimates were based on the percentage that cancer diagnoses occupy within the global molecular diagnostics market and more specifically, the percentage of diagnoses of blood cancer. The platform-based cancer diagnoses market in the Asia-Pacific region is projected to growth at an average annual rate of Forecast of domestic markets for blood cancer molecular diagnostics kits [ 8 ].
As of , Roche had the largest market share of the global molecular diagnostics market, comprising The market concentration is high, as the market share of the three top-ranked companies, namely Roche, Hologic, and Qiagen, totaled Companies participating in the blood cancer diagnostics market include InVivoScribe, Asuragen.
InVivoScribe is a global company that has provided clonality and biomarker test solutions with specializations in oncology, customized molecular diagnostics, and customized molecular medicine.
The kits and reagents from this company is used in around medical and research institutes in 65 countries worldwide. Asuragen, which stemmed from the University of Texas, was established in and sells molecular diagnostics products based on miRNA. Cancer Genetics Inc. Cepheid develops, manufactures and sells genetic analysis products for clinical trials. The technical focus of this company is on the integration and automation of genetic analysis procedures including sample preparation, DNA amplification and detection.
SkylineDx is a company that branched off from the Erasmus University Medical Center Rotterdam, Netherlands that has developed and commercialized blood cancer diagnostic products based on microarray platforms. In September SkylineDx acquired the IP for microarray testing and Skyline diagnostics and established a new company. Established in , Sequenta Inc. In the field of blood cancer molecular diagnostics, the domestic market size is smaller than that of the global market, and there are not many participating companies, but the development of related products has been underway at a few companies such as Seegene and BioSewoom.
The cancer diagnoses market is projected to grow due to technological advances, an increase in cancer patients, and a surge in the elderly population. Furthermore, the molecular diagnostics market is expected to grow significantly as it demonstrates is ability to perform genetic tests that were previously unavailable and replaces the existing clinical chemistry, immunology, and microbiological tests.
Cancer molecular diagnostics is led by global companies such as Roche, Qiagens and Becton Abbott laboratories. Companies competing in the market for blood cancer molecular diagnostics kits include InVivoScribe, Asuragen. Biological Dynamics, and Cancer Genetics, and it appears that the market competition is not likely to change significantly because the technology barriers remain high. The majority of the blood cancer molecular diagnostics kits used in South Korea is imports.
The global market for next-generation cancer diagnoses is projected to follow an annual average growth rate of In conclusion, blood cancer molecular diagnostics kits represent the leading achievement in molecular diagnostics technology with the highest accuracy among available in vitro diagnostic devices, and we anticipate that the demand will continue to increase due to the rising number of cancer patients and the shift of priorities in the medical field from treatment to prevention.
Small and Medium Business Administration: Technology roadmap for small and medium-sized enterprises — Jeon B-H: Developments in the identification of biomarkers for diagnosing diseases using blood. BRIC View. Ministry of Food and Drug Safety: Report on the production, export and import of medical devices — Technologies and global markets. Download references. JHS performed market analysis and drafted the manuscript.