المؤلفون: Vidula, Neelima, Greenberg, Sally, Petrillo, Laura, Hwang, Jimmy, Melisko, Michelle, Goga, Andrei, Moasser, Mark, Magbanua, Mark, Park, John W, Rugo, Hope S

المصدر: NPJ breast cancer. 7(1)

مصطلحات موضوعية: Clinical Research, Breast Cancer, Cancer

الوصف: We evaluated disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) in patients with stage I-III breast cancer with >4 MM/mL DTC at baseline who received adjuvant zoledronic acid (ZOL). ZOL was administered every 4 weeks for 24 months, and patients underwent bone marrow aspiration at baseline, and 12 and 24 months of ZOL. Complete DTC response ( 30/mL and CTC > 0.8/mL were significantly associated with recurrence and death. Serial reduction in DTCs occurred. Higher baseline DTC > 30/mL and CTC > 0.8/mL correlated with recurrence and death.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/95p2f4bbTest

المؤلفون: Magbanua, Mark Jesus M, Hendrix, Laura H, Hyslop, Terry, Barry, William T, Winer, Eric P, Hudis, Clifford, Toppmeyer, Deborah, Carey, Lisa Anne, Partridge, Ann H, Pierga, Jean-Yves, Fehm, Tanja, Vidal-Martínez, José, Mavroudis, Dimitrios, Garcia-Saenz, Jose A, Stebbing, Justin, Gazzaniga, Paola, Manso, Luis, Zamarchi, Rita, Antelo, María Luisa, De Mattos-Arruda, Leticia, Generali, Daniele, Caldas, Carlos, Munzone, Elisabetta, Dirix, Luc, Delson, Amy L, Burstein, Harold J, Qadir, Misbah, Ma, Cynthia, Scott, Janet H, Bidard, François-Clément, Park, John W, Rugo, Hope S

المصدر: Journal of the National Cancer Institute. 113(4)

مصطلحات موضوعية: Cancer, Prevention, Breast Cancer, Clinical Research, Breast Neoplasms, Female, Humans, Neoplastic Cells, Circulating, Prognosis, Progression-Free Survival, Proportional Hazards Models, Reproducibility of Results, Retrospective Studies, Treatment Outcome, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/376347vbTest

المؤلفون: Magbanua, Mark Jesus M, Savenkov, Oleksandr, Asmus, Erik J, Ballman, Karla V, Scott, Janet H, Park, John W, Dickler, Maura, Partridge, Ann, Carey, Lisa A, Winer, Eric P, Rugo, Hope S

المصدر: Clinical Cancer Research. 26(18)

مصطلحات موضوعية: Clinical Research, Breast Cancer, Cancer, Adult, Aged, Aged, 80 and over, Bevacizumab, Breast Neoplasms, Cell Count, Chemotherapy, Adjuvant, Female, Humans, Letrozole, Middle Aged, Neoplastic Cells, Circulating, Predictive Value of Tests, Prognosis, Progression-Free Survival, Receptors, Estrogen, Receptors, Progesterone, Survival Rate, Young Adult, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeWe evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503).Experimental designBlood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models.ResultsOf 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12-1.97] and OS (HR, 2.08; 95% CI, 1.49-2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58-3.07) and death (HR, 3.4; 95% CI, 2.36-4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54-3.47) and OS (HR, 2.6; 95% CI, 1.59-4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients.ConclusionsCTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4144d187Test

المؤلفون: Magbanua, Mark Jesus M, Yau, Christina, Wolf, Denise M, Lee, Jin Sun, Chattopadhyay, Aheli, Scott, Janet H, Bowlby-Yoder, Erin, Hwang, E Shelley, Alvarado, Michael, Ewing, Cheryl A, Delson, Amy L, Veer, Laura J van't, Esserman, Laura, Park, John W

المصدر: Clinical Cancer Research. 25(17)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Breast Cancer, Cancer, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Bone Marrow, Breast Neoplasms, Female, Follow-Up Studies, Humans, Middle Aged, Neoplastic Cells, Circulating, Prognosis, Survival Rate, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis

الوصف: PurposeWe examined the prognostic impact of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) detected at the time of surgery in 742 untreated patients with early breast cancer.Experimental designDTCs in bone marrow were enumerated using the EPCAM-based immunomagnetic enrichment and flow cytometry (IE/FC) assay. CTCs in blood were enumerated either by IE/FC or CellSearch. Median follow-up was 7.1 years for distant recurrence-free survival (DRFS) and 9.1 years for breast cancer-specific survival (BCSS) and overall survival (OS). Cox regressions were used to estimate hazard ratios for DRFS, BCSS, and OS in all patients, as well as in hormone receptor-positive (HR-positive, 87%) and HR-negative (13%) subsets.ResultsIn multivariate models, CTC positivity by IE/FC was significantly associated with reduced BCSS in both all (n = 288; P = 0.0138) and HR-positive patients (n = 249; P = 0.0454). CTC positivity by CellSearch was significantly associated with reduced DRFS in both all (n = 380; P = 0.0067) and HR-positive patients (n = 328; P = 0.0002). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC (n = 273), double positivity (CTC+/DTC+, 8%) was significantly associated with reduced DRFS (P = 0.0270), BCSS (P = 0.0205), and OS (P = 0.0168). In HR-positive patients, double positivity (9% of 235) was significantly associated with reduced DRFS (P = 0.0285), BCSS (P = 0.0357), and OS (P = 0.0092).ConclusionsDetection of CTCs in patients with HR-positive early breast cancer was an independent prognostic factor for DRFS (using CellSearch) and BCSS (using IE/FC). Simultaneous detection of DTCs provided additional prognostic power for outcome, including OS.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1fg46842Test

المؤلفون: Wulfkuhle, Julia D, Yau, Christina, Wolf, Denise M, Vis, Daniel J, Gallagher, Rosa I, Brown-Swigart, Lamorna, Hirst, Gillian, Voest, Emile E, DeMichele, Angela, Hylton, Nola, Symmans, Fraser, Yee, Douglas, Esserman, Laura, Berry, Donald, Liu, Minetta, Park, John W, Wessels, Lodewyk FA, Van't Veer, Laura, Petricoin, Emanuel F

المصدر: JCO Precision Oncology. 2(2)

مصطلحات موضوعية: Genetics, Cancer, Clinical Research, Breast Cancer

الوصف: In the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2), the pan-erythroblastic oncogene B inhibitor neratinib was available to all hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subtypes and graduated in the HR-negative/HER2-positive signature. We hypothesized that neratinib response may be predicted by baseline HER2 epidermal growth factor receptor (EGFR) signaling activation/phosphorylation levels independent of total levels of HER2 or EGFR proteins. Complete experimental and response data were available for between 130 and 193 patients. In qualifying analyses, which used logistic regression and treatment interaction analysis, 18 protein/phosphoprotein, 10 mRNA, and 12 DNA biomarkers that related to HER family signaling were evaluated. Exploratory analyses used Wilcoxon rank sum and t tests without multiple comparison correction. HER pathway DNA biomarkers were either low prevalence or nonpredictive. In expression biomarker analysis, only one gene (STMN1) was specifically associated with response to neratinib in the HER2-negative subset. In qualifying protein/phosphoprotein analyses that used reverse phase protein microarrays, six HER family markers were associated with neratinib response. After analysis was adjusted for HR/HER2 status, EGFR Y1173 (pEGFR) showed a significant biomarker-by-treatment interaction (P = .049). Exploratory analysis of HER family signaling in patients with triple-negative (TN) disease found that activation of EGFR Y1173 (P = .005) and HER2 Y1248 (pHER2) (P = .019) were positively associated with pathologic complete response. Exploratory analysis in this pEGFR/pHER2-activated TN subgroup identified elevated levels of estrogen receptor α (P < .006) in these patients. Activation of HER family phosphoproteins associates with response to neratinib, but only EGFR Y1173 and STMN1 appear to add value to the graduating signature. Activation of HER2 and EGFR in TN tumors may identify patients whose diseases respond to neratinib and implies that there is a subset of patients with TN disease who paradoxically exhibit HER family signaling activation and may achieve clinical benefit with neratinib; this concept must be validated in future studies.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5zk1h2jdTest

المؤلفون: Magbanua, Mark Jesus M, Rugo, Hope S, Wolf, Denise M, Hauranieh, Louai, Roy, Ritu, Pendyala, Praveen, Sosa, Eduardo V, Scott, Janet H, Lee, Jin Sun, Pitcher, Brandelyn, Hyslop, Terry, Barry, William T, Isakoff, Steven J, Dickler, Maura, Veer, Laura van't, Park, John W

المصدر: Clinical Cancer Research. 24(6)

مصطلحات موضوعية: Human Genome, Breast Cancer, Genetics, Biotechnology, Prevention, Cancer, Clinical Research, Good Health and Well Being, Biomarkers, Tumor, Breast Neoplasms, Cell Line, Tumor, Comparative Genomic Hybridization, Epithelial Cell Adhesion Molecule, Female, Gene Expression Profiling, Genomics, Humans, Kaplan-Meier Estimate, MCF-7 Cells, Neoplasm Metastasis, Neoplastic Cells, Circulating, Receptor, ErbB-2, Single-Cell Analysis, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1-ERBB2-, 48% ESR1+ERBB2-, and 27% ERBB2+ Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486-99. ©2018 AACR.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/27c9s1j9Test

المؤلفون: Zhou, Yu, Zou, Hao, Yau, Christina, Zhao, Lequn, Hall, Steven C, Drummond, Daryl C, Farr-Jones, Shauna, Park, John W, Benz, Christopher C, Marks, James D

المصدر: Protein Engineering Design and Selection. 31(1)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Breast Cancer, Women's Health, Cancer, 5.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Antibodies, Neoplasm, Antibody Affinity, Antibody Specificity, Breast Neoplasms, Female, Humans, MCF-7 Cells, Neoplasm Proteins, Single-Chain Antibodies, basaloid breast cancer, cancer target discovery, cell selection, internalizing single chain Fv antibody, phage display, Chemical Sciences, Technology, Biophysics, Biochemistry and cell biology, Industrial biotechnology

الوصف: We present a strategy to discover recombinant monoclonal antibodies (mAbs) to specific cancers and demonstrate this approach using basal subtype breast cancers. A phage antibody library was depleted of antibodies to common cell surface molecules by incubation with luminal breast cancer cell lines, and then selected on a single basal-like breast cancer cell line (MDA-MB-231) for binding associated receptor-mediated endocytosis. Additional profiling against two luminal and four basal-like cell lines revealed 61 unique basal-specific mAbs from a pool of 1440 phage antibodies. The unique mAbs were further screened on nine basal and seven luminal cell lines to identify those with the greatest affinity, specificity, and internalizing capability for basal-like breast cancer cells. Among the internalizing basal-specific mAbs were those recognizing four transmembrane receptors (EphA2, CD44, CD73 and EGFR), identified by immunoprecipitation-mass spectrometry and yeast-displayed antigen screening. Basal-like breast cancer expression of these four receptors was confirmed using a bioinformatic approach, and expression microarray data on 683 intrinsically subtyped primary breast tumors. This overall approach, which sequentially employs phage display antibody library selection, antigen identification and bioinformatic confirmation of antigen expression by cancer subtypes, offers efficient production of high-affinity mAbs with diagnostic and therapeutic utility against specific cancer subtypes.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/30w0m2rsTest
https://escholarship.org/content/qt30w0m2rs/qt30w0m2rs.pdfTest

المؤلفون: Magbanua, Mark Jesus M, Rugo, Hope S, Hauranieh, Louai, Roy, Ritu, Scott, Janet H, Lee, Jen Chieh, Hsiao, Feng, Sosa, Eduardo V, van’t Veer, Laura, Esserman, Laura J, Park, John W

المصدر: npj Breast Cancer. 4(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Stem Cell Research, Human Genome, Clinical Research, Breast Cancer, Clinical sciences, Oncology and carcinogenesis, Epidemiology

الوصف: 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.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/89g757dzTest

المؤلفون: Alkhafaji, Silver, Wolf, Denise M., Magbanua, Mark Jesus M., J. van 't Veer, Laura, Park, John W., Esserman, Laura, Mukhtar, Rita A.

المصدر: NPJ Breast Cancer; 2/26/2024, Vol. 10 Issue 1, p1-10, 10p

المؤلفون: Park, John W, Liu, Minetta C, Yee, Douglas, Yau, Christina, van 't Veer, Laura J, Symmans, W Fraser, Paoloni, Melissa, Perlmutter, Jane, Hylton, Nola M, Hogarth, Michael, DeMichele, Angela, Buxton, Meredith B, Chien, A Jo, Wallace, Anne M, Boughey, Judy C, Haddad, Tufia C, Chui, Stephen Y, Kemmer, Kathleen A, Kaplan, Henry G, Isaacs, Claudine, Nanda, Rita, Tripathy, Debasish, Albain, Kathy S, Edmiston, Kirsten K, Elias, Anthony D, Northfelt, Donald W, Pusztai, Lajos, Moulder, Stacy L, Lang, Julie E, Viscusi, Rebecca K, Euhus, David M, Haley, Barbara B, Khan, Qamar J, Wood, William C, Melisko, Michelle, Schwab, Richard, Helsten, Teresa, Lyandres, Julia, Davis, Sarah E, Hirst, Gillian L, Sanil, Ashish, Esserman, Laura J, Berry, Donald A

المصدر: New England Journal of Medicine. 375(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Clinical Research, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Bayes Theorem, Biomarkers, Tumor, Breast Neoplasms, Female, Humans, Middle Aged, Neoadjuvant Therapy, Paclitaxel, Quinolines, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Trastuzumab, I-SPY 2 Investigators, Receptor, erbB-2, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences

الوصف: BackgroundThe heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery).MethodsWe used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature.ResultsNeratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%.ConclusionsNeratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4xs2222bTest