| 1. |
- Cirenajwis, Helena, et al.
(författare)
-
Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
-
Tidskriftsartikel (refereegranskat)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
|
|
| 2. |
- Culhane, A C, et al.
(författare)
-
Molecular profiling of breast cancer: transcriptomic studies and beyond
- 2007
-
Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-9071 .- 1420-682X. ; 64:24, s. 3185-3200
-
Forskningsöversikt (refereegranskat)abstract
- Utilisation of 'omics' technologies, in particular gene expression profiling, has increased dramatically in recent years. In basic research, high-throughput profiling applications are increasingly used and may now even be considered standard research tools. In the clinic, there is a need for better and more accurate diagnosis, prognosis and treatment response indicators. As such, clinicians have looked to omics technologies for potential biomarkers. These prediction profiling studies have in turn attracted the attention of basic researchers eager to uncover biological mechanisms underlying clinically useful signatures. Here we highlight some of the seminal work establishing the arrival of the omics, in particular transcriptomics, in breast cancer research and discuss a sample of the most current applications. We also discuss the challenges of data analysis and integrated data analysis with emphasis on utilising the current publicly available gene expression datasets.
|
|
| 3. |
- Dahlgren, Malin, et al.
(författare)
-
CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer.
- 2023
-
Ingår i: BMC Research Notes. - 1756-0500. ; 16:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development.Results: CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
|
|
| 4. |
- Hansen, Christian, et al.
(författare)
-
Wnt-5a-induced Phosphorylation of DARPP-32 Inhibits Breast Cancer Cell Migration in a CREB-dependent Manner
- 2009
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:40, s. 27533-27543
-
Tidskriftsartikel (refereegranskat)abstract
- Tumor cell migration plays a central role in the process of cancer metastasis. We recently identified dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) as an antimigratory phosphoprotein in breast cancer cells. Here we link this effect of DARPP-32 to Wnt-5a signaling by demonstrating that recombinant Wnt-5a triggers cAMP elevation at the plasma membrane and Thr34-DARPP-32 phosphorylation in MCF-7 cells. In agreement, both protein kinase A (PKA) inhibitors and siRNA-mediated knockdown of Frizzled-3 receptor or G alpha(s) expression abolished Wnt-5a-induced phosphorylation of DARPP-32. Furthermore, Wnt-5a induced DARPP-32-dependent inhibition of MCF-7 cell migration. Phospho-Thr-34-DARPP-32 interacted with protein phosphatase-1 (PP1) and potentiated the Wnt-5a-mediated phosphorylation of CREB, a well-known PP1 substrate, but had no effect on CREB phosphorylation by itself. Moreover, inhibition of the Wnt-5a/DARPP-32/CREB pathway, by expression of dominant negative CREB (DN-CREB), diminished the antimigratory effect of Wnt-5a-induced phospho-Thr-34-DARPP-32. Phalloidin-staining revealed that that the presence of phospho-Thr-34-DARPP-32 in MCF-7 cells results in reduced filopodia formation. In accordance, the activity of the Rho GTPase Cdc42, known to be crucial for filopodia formation, was reduced in MCF-7 cells expressing phospho-Thr-34-DARPP- 32. The effects of DARPP-32 on cell migration and filopodia formation could be reversed in T47D breast cancer cells that were depleted of their endogenous DARPP-32 by siRNA targeting. Consequently, Wnt-5a activates a Frizzled-3/G alpha(s)/cAMP/PKA signaling pathway that triggers a DARPP-32- and CREB-dependent antimigratory response in breast cancer cells, representing a novel mechanism whereby Wnt-5a can inhibit breast cancer cell migration.
|
|
| 5. |
- Harbst, Katja, et al.
(författare)
-
Molecular and genetic diversity in the metastatic process of melanoma.
- 2014
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 233:1, s. 39-50
-
Tidskriftsartikel (refereegranskat)abstract
- Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.
|
|
| 6. |
- Holm, Karolina, et al.
(författare)
-
Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
- 2012
-
Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891 .- 1878-0261. ; 6:5, s. 494-506
-
Tidskriftsartikel (refereegranskat)abstract
- Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.
|
|
| 7. |
- Howlin, Jillian, et al.
(författare)
-
Loss of CITED1, an MITF regulator, drives a phenotype switch in vitro and can predict clinical outcome in primary melanoma tumours.
- 2015
-
Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- CITED1 is a non-DNA binding transcriptional co-regulator whose expression can distinguish the 'proliferative' from 'invasive' signature in the phenotype-switching model of melanoma. We have found that, in addition to other 'proliferative' signature genes, CITED1 expression is repressed by TGFβ while the 'invasive' signature genes are upregulated. In agreement, CITED1 positively correlates with MITF expression and can discriminate the MITF-high/pigmentation tumour molecular subtype in a large cohort (120) of melanoma cell lines. Interestingly, CITED1 overexpression significantly suppressed MITF promoter activation, mRNA and protein expression levels while MITF was transiently upregulated following siRNA mediated CITED1 silencing. Conversely, MITF siRNA silencing resulted in CITED1 downregulation indicating a reciprocal relationship. Whole genome expression analysis identified a phenotype shift induced by CITED1 silencing and driven mainly by expression of MITF and a cohort of MITF target genes that were significantly altered. Concomitantly, we found changes in the cell-cycle profile that manifest as transient G1 accumulation, increased expression of CDKN1A and a reduction in cell viability. Additionally, we could predict survival outcome by classifying primary melanoma tumours using our in vitro derived 'CITED1-silenced' gene expression signature. We hypothesize that CITED1 acts a regulator of MITF, functioning to maintain MITF levels in a range compatible with tumourigenesis.
|
|
| 8. |
- Howlin, Jillian, et al.
(författare)
-
Pubertal mammary gland development: Insights from mouse models
- 2006
-
Ingår i: Journal of Mammary Gland Biology and Neoplasia. - : Springer Science and Business Media LLC. - 1083-3021 .- 1573-7039. ; 11:3-4, s. 283-297
-
Forskningsöversikt (refereegranskat)abstract
- During puberty the mammary gland develops from a rudimentary tree to a branched epithelial network of ducts which can support alveolar development and subsequent milk production during pregnancy and lactation. This process involves growth, proliferation, migration, branching, invasion, apoptosis and above all, tight regulation which allows these processes to take place simultaneously during the course of just a few weeks to create an adult gland. The process is under hormonal control and is thus coordinated with reproductive development. Mouse models, with overexpressed or knocked-out genes, have highlighted a number of pubertal mammary gland phenotypes and given significant insight into the regulatory mechanisms controlling this period of development. Here we review the published findings of the wide range of gene-manipulated mammary mouse models, documenting the common pubertal mammary gland phenotypes observed, and summarizing their contribution to our current understanding of how pubertal mammary gland development occurs.
|
|
| 9. |
- Howlin, Jillian, et al.
(författare)
-
TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells
- 2008
-
Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:2
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Amplification of the TNK2 gene in primary tumours correlates with poor prognosis. In accordance, TNK2 overexpression was shown to promote invasion of cancer cells - but the mechanism by which TNK2 mediates these effects is unresolved. TNK2 was suggested to regulate Cdc42-driven migration by activation of breast cancer antioestrogen resistance 1 (BCAR1); however, distinct from this effect is evidence for a role of TNK2 in the regulation of epidermal growth factor receptor (EGFR) endocytosis and degradation. In the present study we sought to investigate whether negative targeting of TNK2 by siRNA could be used to inhibit cancer cell invasion, to establish the contribution of its effect on the EGFR and to consequently attempt to resolve the issue of TNK2's mechanism of action. Methods We used siRNA to knockdown expression of TNK2 and its proposed effector BCAR1 in order to analyse the effect of this knockdown on cancer cell behaviour in vitro. We examined morphological changes using phase-contrast microscopy and immunohistochemistry. Functional parameters examined included apoptosis, proliferation, migration and invasion. We also performed flow cytometry analysis to examine EGFR cell surface expression and carried out western blot to examine the total EGFR levels. Results We observed that targeting of TNK2 by siRNA in breast cancer cells resulted in distinct morphological changes characterised by a stellate appearance and an absence of protrusions at membrane edges. These changes were not recapitulated upon siRNA targeting of BCAR1. We thus hypothesised that a component of the effects induced by TNK2 may be independent of BCAR1. Consistent with the idea of an alternative mechanism for TNK2, we observed that TNK2 associates with activated EGFR in breast cancer cells in a TNK2-kinase-independent manner. Furthermore, we demonstrated that TNK2 functions to maintain EGFRs on the cell surface. We could demonstrate that the main functional effect of activating these surface EGFRs in breast cancer cells is stimulation of migration. In accordance, TNK2 silencing by siRNA led to a significant reduction in cell surface EGFR and to a concomitant decrease in the migratory and invasive capacity of breast cancer cells. Conclusion Our data suggest that TNK2 can enhance migration and invasion of breast cancer cells via preservation of EGFR expression, notwithstanding its previously reported signalling via BCAR1, explaining its oncogenic behaviour in vitro and correlation with metastatic human breast cancer in vivo.
|
|
| 10. |
- Jenei, Veronika, et al.
(författare)
-
A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion.
- 2009
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:46, s. 19473-19478
-
Tidskriftsartikel (refereegranskat)abstract
- The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGFbeta1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGFbeta1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGFbeta1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca(2+) signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers.
|
|
| 11. |
- Lauss, Martin, et al.
(författare)
-
Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.
- 2015
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 135:7, s. 1820-1828
-
Tidskriftsartikel (refereegranskat)abstract
- The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes and dermal fibroblasts, and utilized The Cancer Genome Atlas (TCGA) data for experimental validation. By integrating DNA methylation and gene expression data we found that hypermethylation of MITF and its co-regulated differentiation pathway genes, corresponded to decreased gene expression levels. In cell lines with a hypermethylated MITF-pathway, over-expression of MITF did not alter the expression level or methylation status of the MITF pathway genes. In contrast however, demethylation treatment of these cell lines induced MITF-pathway activity, confirming that gene-regulation was controlled via methylation. The discovery that the activity of the master regulator of pigmentation, MITF, and its downstream targets may be regulated by hypermethylation has significant implications for understanding the development and evolvement of melanoma.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.61.
|
|
| 12. |
- McBryan, Jean, et al.
(författare)
-
Amphiregulin: Role in mammary gland development and breast cancer
- 2008
-
Ingår i: Journal of Mammary Gland Biology and Neoplasia. - : Springer Science and Business Media LLC. - 1083-3021 .- 1573-7039. ; 13:2, s. 159-169
-
Tidskriftsartikel (refereegranskat)abstract
- Extensive epithelial cell proliferation underlies the ductal morphogenesis of puberty that generates the mammary tree that will eventually fill the fat pad. This estrogen-dependent process is believed to be essentially dependent on locally produced growth factors that act in a paracrine fashion. EGF-like growth factor ligands, acting through EGF receptors are some of the principal promoters of pubertal ductal morphogenesis. Amphiregulin is the most abundant EGF-like growth factor in the pubertal mammary gland. Its gene is transcriptionally regulated by ER alpha, and recent evidence identifies it as a key mediator of the estrogen-driven epithelial cell proliferation of puberty: The pubertal deficiency in mammary gland ductal morphogenesis in ER alpha, amphiregulin, and EGFR knockout mice phenocopy each other. As a prognostic indicator in human breast cancer, amphiregulin indicates an outcome identical to that predicted by ER alpha presence. Despite this, a range of studies both on preneoplastic human breast tissue and on cell culture based models of breast cancer, suggest a possibly significant role for amphiregulin in driving human breast cancer progression. Here we summarise our current understanding of amphiregulin's contribution to mammary gland development and breast cancer progression.
|
|
| 13. |
- McBryan, J, et al.
(författare)
-
ERalpha-CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis
- 2007
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 26:44, s. 6406-6419
-
Tidskriftsartikel (refereegranskat)abstract
- Expression microarray analysis identified over 930 genes regulated during puberty in the mouse mammary gland. Most prominent were genes whose expression increased in parallel with pubertal development and remained high thereafter. Members of the Wnt, transforming growth factor-beta and oestrogen-signalling pathways were significantly overrepresented. Comparison to expression data from CITED1 knockout mice identified a subset of oestrogen-responsive genes displaying altered expression in the absence of CITED1. Included in this subset are stanniocalcin2 (Stc2) and amphiregulin (Areg). Chromatin immunoprecipitation revealed that ERalpha binds to oestrogen response elements in both the Stc2 and Areg genes in the mammary gland during puberty. Additionally, CITED1 and ERalpha localize to the same epithelial cells of the pubertal mammary gland, supporting a role for interaction of these two proteins during normal development. In a human breast cancer data set, expression of Stc2, Areg and CITED1 parallel that of ERalpha. Similar to ERalpha, CITED1 expression correlates with good outcome in breast cancer, implying that potential maintenance of the ERalpha-CITED1 co-regulated signalling pathway in breast tumours can indicate good prognosis.
|
|
| 14. |
- McBryan, Jean, et al.
(författare)
-
Pubertal mammary gland development : Elucidation of in vivo morphogenesis using Murine models
- 2017
-
Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745. ; 1501, s. 77-114
-
Bokkapitel (refereegranskat)abstract
- During the past 25 years, the combination of increasingly sophisticated gene targeting technology with transplantation techniques has allowed researchers to address a wide array of questions about postnatal mammary gland development. These in turn have significantly contributed to our knowledge of other branched epithelial structures. This review chapter highlights a selection of the mouse models exhibiting a pubertal mammary gland phenotype with a focus on how they have contributed to our overall understanding of in vivo mammary morphogenesis. We discuss mouse models that have enabled us to assign functions to particular genes and proteins and, more importantly, have determined when and where these factors are required for completion of ductal outgrowth and branch patterning. The reason for the success of the mouse mammary gland model is undoubtedly the suitability of the postnatal mammary gland to experimental manipulation. The gland itself is very amenable to investigation and the combination of genetic modification with accessibility to the tissue has allowed an impressive number of studies to inform biology. Excision of the rudimentary epithelial structure postnatally allows genetically modified tissue to be readily transplanted into wild type stroma or vice versa, and has thus defined the contribution of each compartment to particular phenotypes. Similarly, whole gland transplantation has been used to definitively discern local effects from indirect systemic effects of various growth factors and hormones. While appreciative of the power of these tools and techniques, we are also cognizant of some of their limitations, and we discuss some shortcomings and future strategies that can overcome them.
|
|
| 15. |
- Olsson, Eleonor, et al.
(författare)
-
Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
- 2015
-
Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 7:8, s. 1034-1047
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
|
|
| 16. |
|
|
