Precision medicine for metastatic breast cancer—limitations and solutions

Arnedos, Mónica; Vicier, Cécile; Loi, Sherene; Lefèbvre, Céline; Michiels, Stefan; Bonnefoi, Hervé; Varga, Andrea

doi:10.1038/nrclinonc.2015.123

Cited by 284 publications

(202 citation statements)

References 96 publications

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“…Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1,(3)(4)(5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6)(7)(8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9,10).…”

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confidence: 99%

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.Sleeping Beauty | breast cancer | TRPS1 | metastasis | tumor suppressors B reast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and basal-like (1-5). Basal-like or triplenegative breast cancer (TNBC) constitutes 10-20% of all breast cancers and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1, 3-5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6-8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9, 10). Mutations in PTEN drive epithelial-mesenchymal transition (EMT) and promote metastasis in TNBC (11-13). Similarly, in mice, heterozygous deletion of Pten induces mammary tumors with basal-like characteristics (14)(15)(16)(17).Despite all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18-26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes. Transposon insertions in tumors thus serve as molecular tags for the high-throughput cloning and identification of cancer genes. In addition, because transposon insertions are PCR-amplified before they are sequenced, insertional mutations in cancer genes that are present in only a small fraction of tumor cells can be identified. Transposon mutagenesis can thus identify genes that are functioning at th...

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confidence: 99%

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Yet despite these improvements, a high death toll remains and is due to the difficult tractability of metastatic disease, which is only poorly affected by these agents. A further complicating issue is the fact that the frequency of mutated drivers such as ER, HER2, phosphatidylinositol 3-kinase catalytic α polypeptide (PIK3CA) and AKR mouse thyoma kinase 1 (AKT1) is low in BC metastases (3). Another critical issue is the heterogeneity of the disease as manifested by the occurence of several histological and molecular subtypes (4).…”

Section: Abstract Despite the Approval Of Several Molecular Therapiementioning

confidence: 99%

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

Weidle

Dickopf

Hintermair

et al. 2018

CGP

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“…Finally, actionable genomic data emerging from these validation studies will be integrated to design clinical trials with available matching molecular agents. 36 The genomic alterations detected by whole genome sequencing led to proof-of-principle trials in which targeted agents were tested in corresponding molecularly defined clinical series. A major cornerstone has been the identification of Her-2 amplification, seen in approximately 15% of patients with breast cancer, which has been associated with increased cellular proliferation, resistance to standard treatment, and thus poorer outcomes.…”

Section: Clinical Applications and Therapeutic Implicationsmentioning

confidence: 99%

The Role of Genomic Profiling in Advanced Breast Cancer: The Two Faces of Janus

Eralp

2016

Translational Oncogenomics

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Recent advances in genomic technology have led to considerable improvement in our understanding of the molecular basis that underpins breast cancer biology. Through the use of comprehensive whole genome genomic profiling by next-generation sequencing, an unprecedented bulk of data on driver mutations, key genomic rearrangements, and mechanisms on tumor evolution has been generated. These developments have marked the beginning of a new era in oncology called "personalized or precision medicine." Elucidation of biologic mechanisms that underpin carcinogenetic potential and metastatic behavior has led to an inevitable explosion in the development of effective targeted agents, many of which have gained approval over the past decade. Despite energetic efforts and the enormous support gained within the oncology community, there are many obstacles in the clinical implementation of precision medicine. Other than the well-known biologic markers, such as ER and Her-2/neu, no proven predictive marker exists to determine the responsiveness to a certain biologic agent. One of the major issues in this regard is teasing driver mutations among the background noise within the bulk of coexisting passenger mutations. Improving bioinformatics tools through electronic models, enhanced by improved insight into pathway dependency may be the step forward to overcome this problem. Next, is the puzzle on spatial and temporal tumoral heterogeneity, which remains to be solved by ultra-deep sequencing and optimizing liquid biopsy techniques. Finally, there are multiple logistical and financial issues that have to be meticulously tackled in order to optimize the use of "precision medicine" in the real-life setting.keywoRds: breast cancer, molecular alterations, genomic profiling, precision medicine, personalized treatment, tumoral heterogeneity SUPPLEMENT: status of cancer Dna sequencing in the clinic CITATIoN:

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Precision medicine for metastatic breast cancer—limitations and solutions

Cited by 284 publications

References 96 publications

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

The Role of Genomic Profiling in Advanced Breast Cancer: The Two Faces of Janus

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