Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms

Lima, Zeinab Safarpour; Ghadamzadeh, Mostafa; Arashloo, Farzad Tahmasebi; Amjad, Ghazaleh; Ebadi, M. R.; Younesi, Ladan

doi:10.1186/s13045-019-0725-6

Cited by 80 publications

(50 citation statements)

References 347 publications

(384 reference statements)

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“…These molecular characteristics are frequently tumoral but also may be nontumoral, such as germline genetic variants and even nonhuman, such as the gut microbiome as has been proposed as predictive of response to immune checkpoint inhibitors. 1,2 One of the first examples of precision oncology was tumor testing for the estrogen receptor in breast cancer, which distinguishes breast tumors sensitive to hormonal treatments from…”

Section: Precision Oncologymentioning

confidence: 99%

VA National Precision Oncology Program

Kelley¹

2020

Federal Practitioner

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Background: The US Department of Veterans Affairs (VA) is the largest integrated health care system in the US. The VA sees about 50,000 new cancer diagnoses each year and provides care for more than 400,000 veterans with cancer. The heterogeneity of molecular testing practice patterns and methods of testing at VA health care facilities and the increasing number and complexity of molecular tests led to the development of national program for precision oncology. Observations: The National Precision Oncology Program (NPOP) provides tumor sequencing and consultative services for the treatment of veterans with cancer. NPOP is used by nearly all VA oncology practices and has now sequenced > 13,000 samples. The initial focus was on advanced-stage nonsquamous non-small cell lung cancer, which has one of the highest number of mutated genes that result in sensitivity to antineoplastic drugs. Recently, testing was expanded to include metastatic prostate cancer and hematologic malignancies with prior approval. The program also offers cell-free DNA (liquid biopsy) and PD-L1 immunohistochemistry analyses. Conclusions: The VA NPOP is one of the largest clinical DNA sequencing programs in the US with integrated consultation services and health informatics resources to facilitate patient care, clinical trials, and health outcomes research. The clinical services of NPOP provide cutting-edge oncology services to veterans throughout VA without exacerbating disparities and will be a national resource for research.

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Section: Precision Oncologymentioning

confidence: 99%

VA National Precision Oncology Program

Kelley¹

2020

Federal Practitioner

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“…Based on epidemiological studies, different factors increasing the risk of breast cancer development have been highlighted. They can be intrinsic, like mutations in BRCA1 or 2, Tp53, ATM, or also PTEN, or extrinsic, like environmental factors or lifestyle [112,113]. In breast cancers with a genetic origin, the most commonly mutated genes are BRCA1 and BRCA2, associated with an increase in cancer risk.…”

Section: Bmp and Breast Cancermentioning

confidence: 99%

A Potential New Mechanism for Bisphenol Molecules to Initiate Breast Cancer through Alteration of Bone Morphogenetic Protein Signaling in Stem Cells and Their Microenvironment

Guyot¹,

Maguer-Satta²

2020

Breast Cancer Biology

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Endocrine disruptors interfere with endocrine-mediated regulations of cell or organ functions. Estrogens are one of the main hormones altered by endocrine disruptors like bisphenol A (BPA). Stem cells are active from embryogenesis to late stages of adult life. Their unique properties, such as an extended lifespan and low cycling features, render these cell privileged targets of long-term exposure to numerous factors. Therefore, stem cells are likely to be affected following exposure to endocrine disruptors. One of the major signaling pathways involved in stem cell regulation is the bone morphogenetic protein (BMP) pathway. The BMP pathway is known for its involvement in numerous physiological and pathophysiological processes. Exposure of human mammary stem cells to pollutants such as BPA initiates fundamental changes in stem cells, in particular by altering major elements of BMP signaling, such as receptor expression and localization. Lastly, BPA and its substitute bisphenol S (BPS) have similar impacts on BMP signaling despite their different ER-binding properties, supporting the hypothesis that their biological effects cannot be extrapolated only from their interaction with ERα66. We review recent discoveries in this field and discuss their implications for cancer diagnosis, prevention, and treatment, as well as their relevance for studies on endocrine disruptors.

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“…HER2 gene amplification, or protein overexpression, is still considered a major mechanism of HER2-driven tumorigenesis and is used as a main predictive biomarker to identify patients who might benefit from therapy with anti-HER2 agents. ere are, thus, many different cancer drugs approved by the US Food and Drug Administration (FDA) that target the deregulation of HER2, including monoclonal antibodies, antibody-drug conjugates, and small-molecule TKIs (tyrosine kinase inhibitors), such as trastuzumab, pertuzumab, lapatinib, trastuzumab-emtansine (T-DM1), and neratinib [19][20][21], as well as others under investigation such as afatinib [7,[22][23][24][25] (Table 1). Molecular studies have shown that HER2-positive breast cancers are heterogeneous and that the different tumors may be classified as HER2enriched or luminal molecular subtypes based on estrogen receptor expression (ER), with implications in their response to targeted therapies [26].…”

Section: Introductionmentioning

confidence: 99%

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Gaibar

Beltrán

Romero‐Lorca

et al. 2020

Journal of Oncology

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In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

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Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms

Cited by 80 publications

References 347 publications

VA National Precision Oncology Program

VA National Precision Oncology Program

A Potential New Mechanism for Bisphenol Molecules to Initiate Breast Cancer through Alteration of Bone Morphogenetic Protein Signaling in Stem Cells and Their Microenvironment

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

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