Gene expression profiles of primary tumors versus circulating tumor cells in metastatic breast cancer.

Onstenk, Wendy; Sieuwerts, Anieta M.; Weekhout, Marleen; Mostert, Bianca; Reijm, Esther A.; Deurzen, Carolien H.M. van; Kraan, Jaco; Jager, Agnes; Seynaeve, Caroline; Peeters, Dieter; Hamberg, Paul; Jongh, Felix E. de; Galen, Anne M. van; Moreno, Raquel Ramirez; Smid, Marcel; Dirix, Luc; Gratama, Jan-Willem; Martens, John W.M.; Foekens, John A.; Sleijfer, Stefan

doi:10.1200/jco.2014.32.15_suppl.11017

Cited by 6 publications

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“…The CTC evaluation reported in the original study (and the present analysis) occurred after the progression of the patients to stage IV (one of the inclusion criteria of the patients enrolled in the study), which can be years after the initial diagnosis and the tumor resection. It is well known that the phenotype and genotype of the primary tumor can substantially differ from the respective genotypic and phenotypic features of the metastatic lesions as the disease progresses [33][34][35][36] with CTCs resembling better the mutational status of metastatic lesions than of primary tumor [37]. Therefore, the HER2 expression on the primary tumor can differ substantially from the status of the metastatic lesions as well the CTCs and tdEVs isolated having an impact on the concordance found.…”

Section: Discussionmentioning

confidence: 99%

HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

et al. 2020

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Background: Tumor-derived extracellular vesicles (tdEVs) and circulating tumor cells (CTCs) in the blood of metastatic cancer patients associate with poor outcomes. In this study, we explored the human epidermal growth factor receptor 2 (HER2) expression on CTCs and tdEVs of metastatic breast cancer patients. Methods: Blood samples from 98 patients (CLCC-IC-2006-04 study) were originally processed with the CellSearch® system using the CTC kit and anti-HER2 as an additional marker in the staining cocktail. CTCs and tdEVs were automatically enumerated from the generated CellSearch images using the open-source ACCEPT software. Results: CTCs and tdEVs were subdivided based on their cytokeratin (CK) and HER2 phenotype into CK+HER2 −, CK−HER2+, and CK+HER2+. The inclusion of anti-HER2 increased the percentage of informative samples with ≥ 1 detectable CTC from 89 to 95%. CK− CTCs and tdEVs correlated equally well with the clinical outcome as CK+ CTCs and tdEVs. Inter-and intra-patient heterogeneity was found for the CTC/tdEV phenotypes, and the presence of 2 or 3 classes of CTCs/tdEVs was associated with worse prognosis compared to a uniform CTC/tdEV phenotype present (1 class). The use of ≥ 7% HER2+CK+ tdEVs can predict HER2 expression of the tissue with 74% sensitivity and specificity using the HER2 amplification status of the primary tumor as a classification variable. Conclusions: HER2 can be detected on CTCs and tdEVs not expressing CK, and these CK− CTCs/tdEVs have similar clinical relevance to CTCs and tdEVs expressing CK. tdEVs perform better than CTCs in predicting the HER2 status of the primary tissue. CTC and tdEV heterogeneity in the blood of patients is inversely associated with overall survival.

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Section: Discussionmentioning

confidence: 99%

HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

et al. 2020

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“…For this study, 140 patients were retrospectively selected from two prospective clinical trials that have been conducted in six hospitals in the Netherlands and Belgium from 2006 till 2015. Both studies enrolled mBC patients that started with a new line of endocrine therapy or chemotherapy (06–248 and 09–405 study) . Blood for enumeration and molecular characterization of CTCs was collected of all patients before start of this new line of therapy.…”

Section: Methodsmentioning

confidence: 99%

Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer

Kruijff

Sieuwerts

Onstenk

et al. 2019

Intl Journal of Cancer

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The androgen receptor (AR) has potential clinical relevance in metastatic breast cancer (mBC) since it might be a treatment target and has been associated with endocrine resistance. A minimal‐invasive way to determine AR expression on metastatic tumor cells is by characterization of circulating tumor cells (CTCs). Here, we assessed AR mRNA expression in CTCs (CTC‐AR) and in matched primary tumor samples from mBC patients representing different breast cancer subtypes. In addition, we explored CTC‐AR‐status in relation to outcome on endocrine therapy. AR, and 92 AR or estrogen receptor (ER) related genes, were measured in CellSearch‐enriched CTCs from 124 mBC patients and in 52 matched FFPE primary tissues using quantitative reverse‐transcriptase PCR. AR in CTCs was considered positive if the expression was 1 standard deviation higher than the expression measured in 11 healthy blood donors. A total of 31% of the mBC patients had AR‐positive (AR+) CTCs. 58% of the matched CTC and primary tumor samples were discordant with respect to AR status, observing both switches from AR+ to AR‐negative (AR‐) and vice versa. There was no statistically significant difference in progression‐free survival for patients treated with ER‐targeting drugs and CTC‐AR‐status (13 AR+/ 37 AR‐ cases, p = 0.28). Thus, AR can be determined in RNA isolated from CTCs, with in our set 31% AR‐positive samples. Given the discordance between AR status in CTC samples and corresponding primary tumors, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.

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“…The patients evaluated in this study were selected from two CTC studies comprising patients receiving endocrine therapy (study 06‐248 (Mostert et al ., ; Onstenk et al ., ; Sieuwerts et al ., ) and study 09‐405 (Reijm et al ., )). Six centers in the Netherlands and Belgium participated in these studies from February 2008 through March 2015.…”

Section: Methodsmentioning

confidence: 99%

“…Details regarding the CTC enumeration and isolation of DNA/RNA from CTCs have been reported previously (Mostert et al ., ; Onstenk et al ., ; Reijm et al ., ; Sieuwerts et al ., ). Briefly, in each patient, 10 mL of blood was drawn in CellSave tubes (Janssen Diagnostics, Raritan, NJ, USA) for CTC enumeration, which was performed on 7.5 mL of blood within 96 h of the blood draw using the CellSearch system (Janssen Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients

et al. 2017

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Mutations and splice variants in the estrogen receptor (ER) gene, ESR1, may yield endocrine resistance in metastatic breast cancer (MBC) patients. These putative endocrine resistance markers are likely to emerge during treatment, and therefore, its detection in liquid biopsies, such as circulating tumor cells (CTCs) and cell‐free DNA (cfDNA), is of great interest. This research aimed to determine whether ESR1 mutations and splice variants occur more frequently in CTCs of MBC patients progressing on endocrine treatment. In addition, the presence of ESR1 mutations was evaluated in matched cfDNA and compared to CTCs. CellSearch‐enriched CTC fractions (≥5/7.5 mL) of two MBC cohorts were evaluated, namely (a) patients starting first‐line endocrine therapy (n = 43, baseline cohort) and (b) patients progressing on any line of endocrine therapy (n = 40, progressing cohort). ESR1 hotspot mutations (D538G and Y537S/N/C) were evaluated in CTC‐enriched DNA using digital PCR and compared with matched cfDNA (n = 18 baseline cohort; n = 26 progressing cohort). Expression of ESR1 full‐length and 4 of its splice variants (∆5, ∆7, 36 kDa, and 46 kDa) was evaluated in CTC‐enriched mRNA. It was observed that in the CTCs, the ESR1 mutations were not enriched in the progressing cohort (8%), when compared with the baseline cohort (5%) (P = 0.66). In the cfDNA, however, ESR1 mutations were more prevalent in the progressing cohort (42%) than in the baseline cohort (11%) (P = 0.04). Three of the same mutations were observed in both CTCs and cfDNA, 1 mutation in CTCs only, and 11 in cfDNA only. Only the ∆5 ESR1 splice variant was CTC‐specific expressed, but was not enriched in the progressing cohort. In conclusion, sensitivity for detecting ESR1 mutations in CTC‐enriched fractions was lower than for cfDNA. ESR1 mutations detected in cfDNA, rarely present at the start of first‐line endocrine therapy, were enriched at progression, strongly suggesting a role in conferring endocrine resistance in MBC.

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Gene expression profiles of primary tumors versus circulating tumor cells in metastatic breast cancer.

Cited by 6 publications

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HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer

Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients

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