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How Next-Generation Sequencing Can Help Treat Breast Cancer

Breast cancer is one of the most common and deadly cancers among women worldwide. It is estimated that more than 2 million new cases and 600,000 deaths occurred in 2020. Breast cancer is a heterogeneous disease, meaning that different tumors can have different genetic and molecular characteristics that affect their behavior and response to treatment. Therefore, finding the best treatment for each patient is a major challenge.

Next-generation sequencing (NGS) is a technology that can analyze the DNA or RNA of a tumor in a fast and comprehensive way. NGS can detect various types of genetic changes, such as mutations, copy number variations, gene fusions, and gene expression levels, that may be relevant for diagnosis, prognosis, and treatment of breast cancer. NGS can also help identify inherited genetic variants that increase the risk of developing breast cancer or other cancers.

In this blog post, we will review some of the applications and benefits of NGS in breast cancer treatment and research.

NGS for Hereditary Breast Cancer Risk Assessment

Some breast cancers are caused by inherited mutations in genes that normally protect the cells from becoming cancerous. These genes are called tumor suppressor genes, and the most well-known ones are BRCA1 and BRCA2. Women who carry mutations in these genes have a high lifetime risk of developing breast and ovarian cancers, and may also have increased risks of other cancers, such as pancreatic and prostate cancers.

Traditionally, genetic testing for hereditary breast cancer was done by sequencing only the BRCA1 and BRCA2 genes. However, with the advancement of NGS technology, it is now possible to test for multiple genes at once using a panel test. A panel test can include other established breast cancer susceptibility genes, such as ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, as well as genes with less clear or undefined risk, such as BARD1, BRIP1, RAD51C, and RAD51D.

A panel test can provide more information about the genetic risk of breast cancer and other cancers, and help guide the management and prevention strategies for patients and their relatives. For example, patients with mutations in BRCA1 or BRCA2 may benefit from prophylactic surgery, intensive screening, or targeted therapy with PARP inhibitors. Patients with mutations in other genes may have different recommendations depending on the type and level of risk associated with each gene.

NGS for Breast Cancer Subtyping and Prognosis

Breast cancer is not a single disease, but a collection of different subtypes that have distinct molecular features and clinical outcomes. The most widely used classification of breast cancer is based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). These receptors are important for the growth and survival of breast cancer cells, and also serve as therapeutic targets. Based on the status of these receptors, breast cancers can be divided into four main subtypes: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), HER2-enriched (ER-, PR-, HER2+), and triple-negative (ER-, PR-, HER2-).

However, this classification is not enough to capture the full diversity and complexity of breast cancer. NGS can provide a more comprehensive and detailed characterization of breast cancer subtypes by analyzing the gene expression profiles, mutations, and copy number variations of hundreds or thousands of genes. NGS can also help identify novel or rare subtypes of breast cancer that may have different prognoses and treatment responses.

For example, NGS can distinguish between different molecular subtypes of triple-negative breast cancer, such as basal-like, claudin-low, immunomodulatory, and mesenchymal. These subtypes have different levels of immune infiltration, stemness, and epithelial-mesenchymal transition, which may affect their sensitivity to immunotherapy, chemotherapy, and targeted therapy. NGS can also identify mutations or amplifications in genes such as PIK3CA, AKT1, ESR1, and FGFR1, that may have prognostic or predictive value for breast cancer patients.

NGS for Breast Cancer Treatment Selection and Monitoring

One of the main goals of NGS in breast cancer is to find genetic alterations that can be targeted by specific drugs, either approved or in clinical trials. These alterations are called actionable or druggable, and they can be mutations, copy number variations, or gene fusions that affect the function of key signaling pathways or proteins involved in cancer development and progression. NGS can help identify these alterations in both primary and metastatic breast cancers, and guide the selection of the most appropriate and effective treatment for each patient.

For example, NGS can detect mutations or amplifications in HER2, which is the target of several drugs, such as trastuzumab, pertuzumab, lapatinib, and tucatinib. NGS can also detect mutations or amplifications in other genes that are involved in the same pathway as HER2, such as ERBB2, ERBB3, and ERBB4, and may confer resistance or sensitivity to HER2-targeted therapy. NGS can also detect mutations or fusions in other genes that are targets of novel or emerging drugs, such as ALK, NTRK, ROS1, RET, and MET.

NGS can also help monitor the response and resistance to treatment by analyzing the tumor DNA that is shed into the blood, called circulating tumor DNA (ctDNA). ctDNA can reflect the genetic profile of the tumor in real time, and can be used to track the changes in tumor burden, clonal evolution, and emergence of resistance mutations during treatment. ctDNA can also help detect minimal residual disease or early recurrence after treatment.

NGS for Breast Cancer Research and Innovation

NGS is not only a powerful tool for clinical practice, but also for research and innovation. NGS can help discover new genes and mechanisms involved in breast cancer development, progression, and metastasis. NGS can also help identify new biomarkers and targets for diagnosis, prognosis, and treatment of breast cancer. NGS can also enable the development of new technologies and platforms for breast cancer detection, analysis, and therapy.

For example, NGS can help develop new methods for liquid biopsy, such as using circulating tumor cells, exosomes, or microRNAs, that can provide more information and insights about the tumor biology and dynamics. NGS can also help develop new methods for spatial transcriptomics, such as using in situ sequencing or imaging, that can reveal the spatial distribution and heterogeneity of gene expression within the tumor microenvironment. NGS can also help develop new methods for immunotherapy, such as using neoantigens, chimeric antigen receptors, or bispecific antibodies, that can enhance the immune recognition and elimination of tumor cells.


NGS is a revolutionary technology that can provide a comprehensive and detailed view of the genetic and molecular landscape of breast cancer. NGS can help assess the hereditary risk, subtype, prognosis, and treatment options for breast cancer patients. NGS can also help monitor the response and resistance to treatment, and detect minimal residual disease or recurrence. NGS can also help discover new genes, mechanisms, biomarkers, and targets for breast cancer diagnosis, prognosis, and treatment. NGS can also enable the development of new technologies and platforms for breast cancer detection, analysis, and therapy. NGS can help improve the outcomes and quality of life of breast cancer patients, and advance the field of breast cancer research and innovation.


(1) Next-Generation Sequencing-Based Biomarkers in Breast Cancer. https://link.springer.com/chapter/10.1007/978-981-32-9620-6_16.

(2) Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-07432-w.

(3) The Utility of Next-Generation Sequencing in Advanced Breast and Gynecologic Cancers: Experience of a Large Tertiary Care Women’s Hospital. https://academic.oup.com/ajcp/article/156/3/455/6174439.

(4) Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice. https://www.mdpi.com/2072-6694/13/18/4564.

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