Circulating microRNAs miR-331 and miR-195 differentiate local luminal a from metastatic breast cancer

BACKGROUND: Breast cancer is the leading cause of cancer related death in women, with metastasis the principle cause of mortality. New non-invasive prognostic markers are needed for the early detection of metastasis, facilitating treatment decision optimisation. MicroRNA (miRNA) are small, non-coding RNAs regulating gene expression and involved in many cellular processes, including metastasis. As biomarkers, circulating miRNAs (in blood) hold great promise for informing diagnosis or monitoring treatment responses. METHODS: Plasma extracted RNA from age matched local Luminal A (n = 4) or metastatic disease (n = 4) were profiled using Next Generation Sequencing. Selected differentially expressed miRNA were validated on a whole blood extracted miRNA cohort [distant metastatic disease (n = 22), local disease (n = 31), healthy controls (n = 21)]. Area Under the Curve (AUC) in Receiver Operating Characteristic (ROC) analyses was performed. RESULTS: Of 4 miRNA targets tested (miR-181a, miR-329, miR-331, miR-195), mir-331 was significantly over-expressed in patients with metastatic disease, compared to patients with local disease (p \u3c 0.001) or healthy controls (p \u3c 0.001). miR-195 was significantly under-expressed in patients with metastatic disease, compared to patients with local disease (p \u3c 0.001) or healthy controls (p = 0.043). In combination, miR-331 and miR-195 produced an AUC of 0.902, distinguishing metastatic from local breast cancer. CONCLUSIONS: We identified and validated two circulating miRNAs differentiating local Luminal A breast cancers from metastatic breast cancers. Further investigation will reveal the molecular role of these miRNAs in metastasis, and determine if they are subtype specific. This work demonstrates the ability of circulating miRNA to identify metastatic disease, and potentially inform diagnosis or treatment effectiveness

Metastatic breast cancer: Patterns of metastasis and novel biomarkers

Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women, with metastatic disease the principle cause of mortality. In recent years great advances have been made in stratifying breast cancer into a variety of subtypes based on morphological appearance, molecular characteristics and genomic signatures, casting light on the diverse intra-tumour and inter-tumour molecular portrait of the disease. In the era of personalized cancer management, it is imperative to further our understanding of the molecular make-up and clinical behaviour of breast cancer disease so as to tailor treatment and surveillance for recurrence appropriately. In this work we demonstrate the disparate metastatic patterns and outcomes following metastasis of the two major histological subtypes of breast cancer. Furthermore, in a retrospective analysis of metastatic breast cancer patients we identified the initial molecular subtype of primary breast cancer may be different to the subtype of the metastatic disease. This can have significant implications for patient survival and treatment strategies. The development of blood-based biomarkers to expedite earlier detection of breast cancer and of recurrence has been the focus of extensive international research in recent years. Mi(cro)RNAs are small, non-coding RNAs that regulate gene expression and are implicated in a variety of key processes driving both the development of breast cancer metastatic cascade. MiRNAs are stable in circulation and can be quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We* identified a variety of miRNAs to potentially distinguish local breast cancer from metastatic breast cancer in the commonest type of breast cancer (Luminal A). This work allowed us to identify and validate selected miRNA on an independent cohort of 74 patients. Two miRNAs (mir-331 and mir-195) showed significantly dysregulation between metastatic disease and local disease and healthy controls. This work sheds further light on the heterogeneity of breast cancer and the diverse patterns and outcomes of metastatic disease, and highlights the potential of blood based miRNA biomarkers to contribute to the evolving management of breast cancer

Metastatic breast cancer: Patterns of metastasis and novel biomarkers

Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women, with metastatic disease the principle cause of mortality. In recent years great advances have been made in stratifying breast cancer into a variety of subtypes based on morphological appearance, molecular characteristics and genomic signatures, casting light on the diverse intra-tumour and inter-tumour molecular portrait of the disease. In the era of personalized cancer management, it is imperative to further our understanding of the molecular make-up and clinical behaviour of breast cancer disease so as to tailor treatment and surveillance for recurrence appropriately. In this work we demonstrate the disparate metastatic patterns and outcomes following metastasis of the two major histological subtypes of breast cancer. Furthermore, in a retrospective analysis of metastatic breast cancer patients we identified the initial molecular subtype of primary breast cancer may be different to the subtype of the metastatic disease. This can have significant implications for patient survival and treatment strategies. The development of blood-based biomarkers to expedite earlier detection of breast cancer and of recurrence has been the focus of extensive international research in recent years. Mi(cro)RNAs are small, non-coding RNAs that regulate gene expression and are implicated in a variety of key processes driving both the development of breast cancer metastatic cascade. MiRNAs are stable in circulation and can be quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We* identified a variety of miRNAs to potentially distinguish local breast cancer from metastatic breast cancer in the commonest type of breast cancer (Luminal A). This work allowed us to identify and validate selected miRNA on an independent cohort of 74 patients. Two miRNAs (mir-331 and mir-195) showed significantly dysregulation between metastatic disease and local disease and healthy controls. This work sheds further light on the heterogeneity of breast cancer and the diverse patterns and outcomes of metastatic disease, and highlights the potential of blood based miRNA biomarkers to contribute to the evolving management of breast cancer

Metastatic breast cancer: Patterns of metastasis and novel biomarkers

Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women, with metastatic disease the principle cause of mortality. In recent years great advances have been made in stratifying breast cancer into a variety of subtypes based on morphological appearance, molecular characteristics and genomic signatures, casting light on the diverse intra-tumour and inter-tumour molecular portrait of the disease. In the era of personalized cancer management, it is imperative to further our understanding of the molecular make-up and clinical behaviour of breast cancer disease so as to tailor treatment and surveillance for recurrence appropriately. In this work we demonstrate the disparate metastatic patterns and outcomes following metastasis of the two major histological subtypes of breast cancer. Furthermore, in a retrospective analysis of metastatic breast cancer patients we identified the initial molecular subtype of primary breast cancer may be different to the subtype of the metastatic disease. This can have significant implications for patient survival and treatment strategies. The development of blood-based biomarkers to expedite earlier detection of breast cancer and of recurrence has been the focus of extensive international research in recent years. Mi(cro)RNAs are small, non-coding RNAs that regulate gene expression and are implicated in a variety of key processes driving both the development of breast cancer metastatic cascade. MiRNAs are stable in circulation and can be quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We* identified a variety of miRNAs to potentially distinguish local breast cancer from metastatic breast cancer in the commonest type of breast cancer (Luminal A). This work allowed us to identify and validate selected miRNA on an independent cohort of 74 patients. Two miRNAs (mir-331 and mir-195) showed significantly dysregulation between metastatic disease and local disease and healthy controls. This work sheds further light on the heterogeneity of breast cancer and the diverse patterns and outcomes of metastatic disease, and highlights the potential of blood based miRNA biomarkers to contribute to the evolving management of breast cancer

Circulating nucleosomes and nucleosome modifications as biomarkers in cancer

Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients

Circulating nucleosomes and nucleosome modifications as biomarkers in cancer

Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients