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Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy.

ABSTRACT: Circulating tumor cells (CTCs) are considered as surrogate markers for prognosticating and evaluating patient treatment responses. Here, 226 blood samples from 92 patients with breast cancer, including patients with newly diagnosed or metastatic refractory cancer, and 16 blood samples from healthy subjects were cultured in laser-ablated microwells. Clusters containing an increasing number of cytokeratin-positive (CK+) cells appeared after 2 weeks, while most blood cells disappeared with time. Cultures were heterogeneous and exhibited two distinct sub-populations of cells: 'Small' (≤ 25 μm; high nuclear/cytoplasmic ratio; CD45-) cells, comprising CTCs, and 'Large' (> 25 μm; low nuclear/cytoplasmic ratio; CD68+ or CD56+) cells, corresponding to macrophage and natural killer-like cells. The Small cell fraction also showed copy number increases in six target genes (FGFR1, Myc, CCND1, HER2, TOP2A and ZNF217) associated with breast cancer. These expanded CTCs exhibited different proportions of epithelial-mesenchymal phenotypes and were transferable for further expansion as spheroids in serum-free suspension or 3D cultures. Cluster formation was affected by the presence and duration of systemic therapy, and its persistence may reflect therapeutic resistance. This novel and advanced method estimates CTC clonal heterogeneity and can predict, within a relatively short time frame, patient responses to therapy.

SUBMITTER: Khoo BL

PROVIDER: S-EPMC4558172 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy.

Khoo Bee Luan BL Lee Soo Chin SC Kumar Prashant P Tan Tuan Zea TZ Warkiani Majid Ebrahimi ME Ow Samuel G W SG Nandi Sayantani S Lim Chwee Teck CT Thiery Jean Paul JP

Oncotarget 20150601 17

Circulating tumor cells (CTCs) are considered as surrogate markers for prognosticating and evaluating patient treatment responses. Here, 226 blood samples from 92 patients with breast cancer, including patients with newly diagnosed or metastatic refractory cancer, and 16 blood samples from healthy subjects were cultured in laser-ablated microwells. Clusters containing an increasing number of cytokeratin-positive (CK+) cells appeared after 2 weeks, while most blood cells disappeared with time. Cu ...[more]

PMID: 26008969

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Project description:BackgroundApproximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression.MethodsCirculating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells.ResultsAberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy.ConclusionsHypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Project description:BackgroundPathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with improved overall survival (OS) in patients with breast cancer, but it is unclear how post-NACT response influences radiation therapy administration in patients presenting with node-positive disease. We sought to determine whether nodal pCR is associated with likelihood of receiving nodal radiation and whether radiation therapy among patients experiencing nodal pCR is associated with improved OS.Methods and materialsClinical N1 (cN1) female breast cancer patients diagnosed during 2010 to 2015 who were ypN0 (ie, nodal pCR; n = 12,341) or ypN1 (ie, residual disease; n = 13,668) after NACT were identified in the National Cancer Database. Multivariate logistic regression was used to identify factors associated with receiving radiation therapy. Cox proportional hazards modeling was used to estimate the association between radiation therapy and adjusted OS.ResultsThe study included 26,009 patients; 43.9% (n = 5423) of ypN0 and 55.3% (n = 7556) of ypN1 patients received nodal radiation. Rates of nodal radiation remained the same over time among ypN0 patients (trend test, P = .29) but increased among ypN1 patients from 49% in 2010 to 59% in 2015 (trend test, P < .001). After adjusting for covariates, nodal pCR (vs no stage change) was associated with decreased likelihood of nodal radiation after mastectomy (∼20% decrease) and lumpectomy (∼30% decrease; both P < .01). After mastectomy, nodal (vs no) radiation conferred no significant survival benefit in ypN0 patients, but it approached significance for ypN1 patients (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.69-0.99, P = .04; overall P = .11). After lumpectomy, nodal radiation was associated with improved adjusted OS for ypN0 (HR, 0.38; 95% CI, 0.22-0.66) and ypN1 patients (HR, 0.44; 95% CI, 0.30-0.66; both P < .001), but this improvement was not significantly greater than that associated with breast-only radiation.ConclusionsypN0 patients were less likely to receive nodal radiation than ypN1 patients were, suggesting that selective omission already occurs and, in the context of limited survival data, could potentially be appropriate for select patients.

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Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy.

Publications

Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy.

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