<i>PIK3CA</i> Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.

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“…Other studies have also detected PIK3CA mutations in CTCs and DTCs that were not found in their corresponding primary tumors. 52–54 …”

Section: Discussionmentioning

confidence: 99%

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

et al. 2018

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“…Indeed, the molecular analysis of CTCs is anticipated to (a) reveal new therapeutic targets, (b) delineate cancer cell signaling, and (c) explore cancer cell dissemination. Such molecular characterization of CTCs has focused on the gene expression [70][71][72] , DNA methylation [73,74] , as well as DNA mutation levels [75,76] . Currently, there are many large-scale translational studies in progress, which will generate critical data and drive CTC analysis and implementation in the clinic, empowering tailor-made therapeutic strategies [77] .…”

Section: A Complementary Role For Liquid Biopsies (And In Particularmentioning

confidence: 99%

Exosomes: A Cancer Theranostics Road Map

Panagiotara

Markou

Lianidou

et al. 2017

Public Health Genomics

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Interindividual variability is yet to be fully characterized, and for this, optimum patient stratification and companion diagnostics are still lacking. Especially when complex disease phenotypes and/or polygenic diseases are considered, patient monitoring and disease management become rather challenging, while acquired resistance to therapy and/or toxicity events are among the unmet needs in the clinic. No doubt, biomarkers are of great importance to disease management and tailor-made theranostics. Microfluidics has gathered great attention lately, mostly due to its low-invasive nature compared to tissue biopsies. Low invasiveness becomes greatly advantageous for microfluidics practices as the latter mirror cell biology revolutionizing cancer diagnostics and management. Recent advances in microfluidics hold the promise of robust clinical diagnostics after they have demonstrated effective exosome separation. We feel that microfluidics-based exosome isolation techniques, if cost-effective, could be implemented in the clinic and/or resource-scarce settings. This article (a) discusses exosomes, (b) comments on the first microfluidic advances in the field of cancer theranostics, (c) presents such advances in exosomes as complementary to liquid biopsies with an emphasis on circulating tumor cells, and (d) proposes a road map for future developments.

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“…PIK3CAm have been detected in CTCs from patients with both early and metastatic breast cancer [21,22]. Despite implementing different methodologies, two studies demonstrated the dynamic nature of the mutation with loss or gain of PIK3CAm detected as tumors progress or recur.…”

Section: Pik3ca Mutations In Breast Cancermentioning

confidence: 99%

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

Al-Sukhun¹,

Lataifeh

Al-Sukhun³

2016

Curr Breast Cancer Rep

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PIK3CA is one of the most commonly mutated oncogenes in breast cancer, albeit at variable distribution among the different biological subtypes. Overall, it appears that PIK3CA mutations are most likely found in tumors with less aggressive characteristics, especially estrogen receptor (ER)-positive, luminal A tumors. Studies assessing its prognostic or predictive role have reported conflicting data, in part due to different methodologies used for detection and small sample sizes. The majority of reports used retrospective data from clinical trials thus could not exclude the effect of treatment heterogeneity when evaluating prognostic factors, and analysis was not subtype specific. Since breast cancer subtypes differ in terms of biology, treatment, and outcomes, it is critical that the effects of PIK3CA mutations on pathophysiology and therapy responsiveness are analyzed independently in each subtype. This short review discusses these issues and the significance of PIK3CA mutations in relation to the expression of HER2 and hormone receptors.

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PIK3CA Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

Cited by 60 publications

References 54 publications

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

Exosomes: A Cancer Theranostics Road Map

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

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