31 results on '"Cobleigh M"'
Search Results
2. A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer
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Miller, K. D., Gradishar, W., Schuchter, L., Sparano, J. A., Cobleigh, M., Robert, N., Rasmussen, H., and Sledge, G. W.
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- 2002
3. Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours
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Oh, D.-Y., primary, Hamilton, E., additional, Hanna, D., additional, Beeram, M., additional, Lee, K.-W., additional, Kang, Y.-K., additional, Chaves, J., additional, Lee, J.-Y., additional, Goodwin, R., additional, Vaklavas, C., additional, Rha, S.-Y., additional, Elimova, E., additional, Mayordomo, J., additional, Ferrario, C., additional, Cobleigh, M., additional, Fortenberry, A., additional, Rowse, G., additional, Gray, T., additional, Lai, R., additional, and Meric Bernstam, F., additional
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- 2019
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4. Abstract PD8-12: Safety and efficacy of palbociclib and radiotherapy in metastatic breast cancer patients: Initial results of a novel combination
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Chowdhary, M, primary, Sen, N, additional, Chowdhary, A, additional, Usha, L, additional, Cobleigh, M, additional, Patel, KR, additional, Wang, D, additional, Barry, PN, additional, and Rao, RD, additional
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- 2019
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5. Abstract P2-10-10: Oncotype Dx testing in patients with synchronous unilateral primary breast cancer
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Clark, M, primary, Coggan, J, additional, Dignam, J, additional, Rao, R, additional, Usha, L, additional, Kabaker, K, additional, and Cobleigh, M, additional
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- 2018
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6. Baseline characteristics and first-line (1L) treatment of patients with HER2+ metastatic breast cancer (MBC) from the SystHERs registry
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Kaufman, P.A., primary, Hurvitz, S.A., additional, O'Shaughnessy, J., additional, Mason, G., additional, Yardley, D.A., additional, Brufsky, A., additional, Rugo, H.S., additional, Cobleigh, M., additional, Swain, S.M., additional, Tripathy, D., additional, Chu, L., additional, Antao, V., additional, Yoo, B., additional, and Jahanzeb, M., additional
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- 2017
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7. First-line treatment patterns by age for patients (pts) with HER2+ metastatic breast cancer (MBC) in the SystHERs registry
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Jahanzeb, M., primary, Tripathy, D., additional, Hurvitz, S.A., additional, O'Shaughnessy, J., additional, Mason, G., additional, Yardley, D.A., additional, Brufsky, A., additional, Rugo, H.S., additional, Cobleigh, M., additional, Swain, S.M., additional, Chu, L., additional, Antao, V., additional, Yoo, B., additional, and Kaufman, P.A., additional
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- 2017
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8. Abstract P5-08-27: Treatment patterns and clinical outcomes in patients with hormone receptor (HR)+ HER2+ metastatic breast cancer and low vs high levels of HR positivity from the SystHERs Registry
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Jahanzeb, M, primary, Tripathy, D, additional, Rugo, H, additional, Swain, S, additional, Kaufman, PA, additional, Mayer, M, additional, Hurvitz, S, additional, O'Shaughnessy, J, additional, Mason, G, additional, Yardley, DA, additional, Brufsky, A, additional, Chu, L, additional, Antao, V, additional, Beattie, M, additional, Yoo, B, additional, and Cobleigh, M, additional
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- 2017
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9. Abstract P5-08-08: Baseline (BL) characteristics, treatment (tx) patterns, and outcomes in patients with hormone receptor (HR)+ vs HR– HER2+ disease from the SystHERs registry
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Cobleigh, M, primary, Yardley, DA, additional, Brufsky, A, additional, Rugo, H, additional, Swain, S, additional, Kaufman, PA, additional, Tripathy, D, additional, Mayer, M, additional, Hurvitz, S, additional, O'Shaughnessy, J, additional, Mason, G, additional, Chu, L, additional, Antao, V, additional, Beattie, M, additional, Yoo, B, additional, and Jahanzeb, M, additional
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- 2017
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10. 61O - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours
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Oh, D.-Y., Hamilton, E., Hanna, D., Beeram, M., Lee, K.-W., Kang, Y.-K., Chaves, J., Lee, J.-Y., Goodwin, R., Vaklavas, C., Rha, S.-Y., Elimova, E., Mayordomo, J., Ferrario, C., Cobleigh, M., Fortenberry, A., Rowse, G., Gray, T., Lai, R., and Meric Bernstam, F.
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- 2019
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11. 275P - First-line treatment patterns by age for patients (pts) with HER2+ metastatic breast cancer (MBC) in the SystHERs registry
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Jahanzeb, M., Tripathy, D., Hurvitz, S.A., O'Shaughnessy, J., Mason, G., Yardley, D.A., Brufsky, A., Rugo, H.S., Cobleigh, M., Swain, S.M., Chu, L., Antao, V., Yoo, B., and Kaufman, P.A.
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- 2017
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12. 274P - Baseline characteristics and first-line (1L) treatment of patients with HER2+ metastatic breast cancer (MBC) from the SystHERs registry
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Kaufman, P.A., Hurvitz, S.A., O'Shaughnessy, J., Mason, G., Yardley, D.A., Brufsky, A., Rugo, H.S., Cobleigh, M., Swain, S.M., Tripathy, D., Chu, L., Antao, V., Yoo, B., and Jahanzeb, M.
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- 2017
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13. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100
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Schneider, B P, primary, Li, L, additional, Shen, F, additional, Miller, K D, additional, Radovich, M, additional, O'Neill, A, additional, Gray, R J, additional, Lane, D, additional, Flockhart, D A, additional, Jiang, G, additional, Wang, Z, additional, Lai, D, additional, Koller, D, additional, Pratt, J H, additional, Dang, C T, additional, Northfelt, D, additional, Perez, E A, additional, Shenkier, T, additional, Cobleigh, M, additional, Smith, M L, additional, Railey, E, additional, Partridge, A, additional, Gralow, J, additional, Sparano, J, additional, Davidson, N E, additional, Foroud, T, additional, and Sledge, G W, additional
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- 2014
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14. Abstract P5-18-24: Population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of various covariates
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Lu, D, primary, Girish, S, additional, Gao, Y, additional, Wang, B, additional, Yi, J-H, additional, Guardino, E, additional, Samant, M, additional, Cobleigh, M, additional, Rimawi, M, additional, Conte, P, additional, and Jin, J, additional
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- 2012
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15. Pathologic Findings in MRI-Guided Needle Core Biopsies of the Breast in Patients with Newly Diagnosed Breast Cancer
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Siziopikou, K. P., primary, Jokich, P., additional, and Cobleigh, M., additional
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- 2011
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16. NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx).
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Cobleigh, M. A., Anderson, S. J., Julian, T. B., Siziopikou, K. P., Arthur, D. W., Rabinovitch, R., Zheng, P., Mamounas, E. P., and Wolmark, N.
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BREAST cancer research , *CELL lines , *APOPTOSIS , *BREAST tumors , *LUMPECTOMY , *CANCER in women - Abstract
Background: A significant amount of DCIS is ER negative and/or overexpresses HER2. This provides an opportunity to test molecular therapy in DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In T-treated HER2+ patients, apoptosis occurs within 1 wk of single agent T use, with T found in ductal aspirates. Ample safety evidence for T exists. T given during whole breast irradiation (WBI) may improve results for lumpectomy (Lx) resected HER2+ DCIS. A trial to examine this question will enhance the understanding of breast tumor biology and the prevention of such tumors and could possibly extend breast-conserving surgery benefits for women with DCIS. Method: After Lx for pure DCIS, each patient's DCIS lesion is centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned to 2 doses of T, 3 weeks apart during WBI or to WBI alone. Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status must be known before randomization. Primary aims are to determine if T decreases ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and OS can be improved with the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 ipsilateral breast cancer events (7.5-8 yrs. after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR- SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 5-31-12, 939 patients have been randomized. NCT00769379Grant support: PHS NCI-U10-CA-69651, -12027, and NCI P30-CA-14599 from the US NCI and Genentech, Inc. [ABSTRACT FROM AUTHOR]
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- 2012
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17. Population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of various covariates.
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Lu, D., Girish, S., Gao, Y., Wang, B., Yi, J.-H., Guardino, E., Samant, M., Cobleigh, M., Rimawi, M., Conte, P., and Jin, J.
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TRASTUZUMAB , *PHARMACOKINETICS , *PHARMACOLOGY , *SERUM , *SULFIDES , *DRUGS - Abstract
Background: Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate composed of the humanized monoclonal antibody trastuzumab, the potent cytotoxic agent DM1 (a microtubule inhibitor), and a stable thioether linker. To estimate typical pharmacokinetic (PK) parameter values and interpatient variability, a population PK model for T-DM1 was previously developed from 1 phase 1 (0.3 to 4.8 mg/kg in qw or q3w regimens) and 2 phase 2 (3.6 mg/kg q3w) trials (Gupta, J Clin Pharmacol2012). The model reported here has been updated with additional data from 2 randomized trials (phase 2 TDM4450g and phase 3 EMILIA, 3.6 mg/kg q3w). Another phase 2 trial (TDM4688g) was used for external validation of the model. The effect of demographic and pathophysiological covariates on the PK of T-DM1 was explored to better understand the clinical factors that might affect exposure and clinical outcome for individual patients. Methods: For the current analysis, 9934 T-DM1 serum concentration-time data points from 671 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a 2-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, or likely to have clinical relevance, were explored for possible correlation with the key T-DM1 PK parameters of clearance (CL) and central volume of distribution (Vc). These covariates include those related to demographics, renal and hepatic function, disease status, and treatment history. Results: The estimated CL for T-DM1 is 0.68 L/day, Vc is 3.13 L, and the terminal half-life is 3.94 days. Interindividual variability (IIV) of the base model is 25.6% and 17.5% for CL and Vc, respectively. Patients with greater body weight, sum of longest dimension of target lesions, serum concentration of shed HER2 extracellular domain, and aspartate aminotransferase concentrations, as well as patients with lower serum albumin and baseline trastuzumab concentrations, have statistically faster CL. Patients with greater body weight also have statistically larger Vc. Incorporation of these covariates (P<0.001 by likelihood ratio test) decreased IIV of CL and Vc to 19.1 % and 11.7%, respectively. All covariates together explain 44.4% and 55.8% of IIV in CL and Vc, respectively. The model sensitivity analysis suggests that a patient with a statistically significant PK covariate value at the 5th or 95th percentile of the population will have a <20% difference in cumulative exposure (as represented by area under the T-DM1 concentration-time curve) compared with a typical patient with a median covariate value. Conclusions: A relatively small IIV for the estimated T-DM1 PK parameters of CL and Vc was observed. None of the evaluated covariates had a clinically meaningful magnitude of effect on T-DM1 exposure (<20% difference for patients with 5th and 95th percentiles vs patients with median value of covariates) that would justify a further dose adjustment. The body weight-based dose of 3.6 mg/kg q3w without further correction for other factors is considered appropriate in ongoing clinical trials. [ABSTRACT FROM AUTHOR]
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- 2012
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18. Correction: Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin‑treated breast cancer patients: a prospective exploratory study.
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Chu J, Tung L, Atallah I, Wei C, Cobleigh M, Rao R, Feinstein SB, Usha L, Banach K, Reiser J, and Okwuosa TM
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- 2024
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19. Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin-treated breast cancer patients: a prospective exploratory study.
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Chu J, Tung L, Atallah I, Wei C, Cobleigh M, Rao R, Feinstein SB, Usha L, Banach K, Reiser J, and Okwuosa TM
- Abstract
Background: Soluble urokinase plasminogen activator receptor is an inflammatory biomarker that may prognosticate cardiovascular outcomes. We sought to determine the associations between soluble urokinase plasminogen activator receptor and established markers of cardiotoxicity in breast cancer patients receiving doxorubicin., Methods: We conducted a prospective cohort study of women with newly diagnosed breast cancer receiving standard-dose doxorubicin (240 mg/m
2 ) at Rush University Medical Center and Rush Oak Park Hospital (Chicago, IL) between January 2017 and May 2019. Left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers (N-terminal prohormone B-type natriuretic peptide, troponin-I, and high-sensitivity C-reactive protein) were measured at baseline and at intervals up to 12-month follow-up after end of treatment. The associations between soluble urokinase plasminogen activator receptor and these endpoints were evaluated using multivariable mixed effects linear regression., Results: Our study included 37 women (mean age 47.0 ± 9.3 years, 60% white) with a median baseline soluble urokinase plasminogen activator receptor level of 2.83 ng/dL. No participant developed cardiomyopathy based on serial echocardiography by one-year follow-up. The median percent change in left ventricular strain was -4.3% at 6-month follow-up and absolute changes in cardiac biomarkers were clinically insignificant. There were no significant associations between soluble urokinase plasminogen activator receptor and these markers of cardiotoxicity (all p > 0.05)., Conclusions: In this breast cancer cohort, doxorubicin treatment was associated with a very low risk for cardiotoxicity. Across this narrow range of clinical endpoints, soluble urokinase plasminogen activator receptor was not associated with markers of subclinical cardiotoxicity. Further studies are needed to clarify the prognostic utility of soluble urokinase plasminogen activator receptor in doxorubicin-associated cardiomyopathy and should include a larger cohort of leukemia and lymphoma patients who receive higher doses of doxorubicin., (© 2024. The Author(s).)- Published
- 2024
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20. Comparison of gut microbiome composition in colonic biopsies, endoscopically-collected and at-home-collected stool samples.
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Nowicki C, Ray L, Engen P, Madrigrano A, Witt T, Lad T, Cobleigh M, and Mutlu EA
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Aim: The goal of this study is to compare microbiome composition in three different sample types in women, namely stool brought from home vs. solid stool samples obtained at the time of an unprepped sigmoidoscopy vs. biopsies of the colonic mucosa at the time of an unprepped sigmoidoscopy, using alpha- and beta-diversity metrics following bacterial 16S rRNA sequencing. The findings may have relevance to health and disease states in which bacterial metabolism has a significant impact on molecules/metabolites that are recirculated between the gut lumen and mucosa and systemic circulation, such as estrogens (as in breast cancer) or bile acids., Methods: Concomitant at-home-collected stool, endoscopically-collected stool, and colonic biopsy samples were collected from 48 subjects (24 breast cancer, 24 control.) After 16S rRNA sequencing, an amplicon sequence variant (ASV) based approach was used to analyze the data. Alpha diversity metrics (Chao1, Pielou's Evenness, Faith PD, Shannon, and Simpson) and beta diversity metrics (Bray-Curtis, Weighted and Unweighted Unifrac) were calculated. LEfSe was used to analyze differences in the abundance of various taxa between sample types., Results: Alpha and beta diversity metrics were significantly different between the three sample types. Biopsy samples were different than stool samples in all metrics. The highest variation in microbiome diversity was noted in the colonic biopsy samples. At-home and endoscopically-collected stool showed more similarities in count-based and weighted beta diversity metrics. There were significant differences in rare taxa and phylogenetically-diverse taxa between the two types of stool samples. Generally, there were higher levels of Proteobacteria in biopsy samples, with significantly more Actinobacteria and Firmicutes in stool (all p < 0.001, q-value < 0.05). Overall, there was a significantly higher relative abundance of Lachnospiraceae and Ruminococcaceae in stool samples (at-home collected and endoscopically-collected) and higher abundances of Tisserellaceae in biopsy samples (all p < 0.001, q-value < 0.05)., Conclusion: Our data shows that different sampling methods can impact results when looking at the composition of the gut microbiome using ASV-based approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nowicki, Ray, Engen, Madrigrano, Witt, Lad, Cobleigh and Mutlu.)
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- 2023
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21. The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer.
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Ma CX, Luo J, Freedman RA, Pluard TJ, Nangia JR, Lu J, Valdez-Albini F, Cobleigh M, Jones JM, Lin NU, Winer EP, Marcom PK, Thomas S, Anderson J, Haas B, Bucheit L, Bryce R, Lalani AS, Carey LA, Goetz MP, Gao F, Kimmick G, Pegram MD, Ellis MJ, and Bose R
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Fulvestrant, Humans, Quinolines, Receptor, ErbB-2 genetics, Receptor, ErbB-2 therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Purpose: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor-positive (ER+) breast cancer., Patients and Methods: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER-)/HER2mut MBC received neratinib monotherapy in an exploratory ER- cohort (n = 5)., Results: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%-62%), 30% (7%-65%), and 25% (1%-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression., Conclusions: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC., (©2022 American Association for Cancer Research.)
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- 2022
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22. Paired tumor sequencing and germline testing in breast cancer management: An experience of a single academic center.
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Elliott E, Speare V, Coggan J, Espenschied C, LaDuca H, Yussuf AF, Burgess K, Gray P, Cobleigh M, Rao R, Patel J, Kuzel T, Buckingham LE, and Usha L
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms therapy, Checkpoint Kinase 2 genetics, Female, Genes, BRCA1, Genes, BRCA2, Genes, p53, Humans, Middle Aged, Pilot Projects, Retrospective Studies, Breast Neoplasms genetics, Germ-Line Mutation
- Abstract
Background: Genetic testing for cancer predisposition is recommended to women with breast cancer who meet the criteria for such testing. After the FDA approvals of the poly ADP ribose polymerase (PARP) inhibitors, olaparib and talazoparib, for treatment of metastatic breast cancer, carrying germline mutations in BRCA1 and BRCA2 genes, the genetic testing result has become critical in their care. With the recent FDA approval of alpelisib for the treatment of PIK3CA-mutated hormone-receptor positive metastatic breast cancer, tumor molecular profiling to identify somatic mutations and potential molecularly targeted agents is increasingly utilized in the treatment of advanced breast cancer., Aim: Combining germline and somatic sequencing (paired testing) offers an advantage over a single technique approach. Our study evaluates the role of paired testing on the management of breast cancer patients., Methods and Results: Forty-three breast cancer patients treated at Rush University Medical Center underwent paired germline and somatic variant testing in 2015 to 2017. A retrospective chart review was conducted with the analysis of demographic, clinical, and genomic data. Three actionable germline variants were found in the CHEK2 (2) and ATM (1) genes. 95% of tumors had somatic mutations. Seventy-seven percent of tumors had genomic alterations targetable with agents approved for breast cancer and 88% had molecular targets for agents approved for other cancers. Clinical examples of such use are described and potential future directions of tumor and paired testing are discussed., Conclusions: Germline variants were present in a relatively small patient group not routinely tested for inherited alterations. Potentially targetable somatic alterations were identified in the majority of breast cancers. Paired testing is a feasible and efficient approach that delivers valuable information for the care of breast cancer patients and eliminates serial testing., (© 2020 The Authors. Cancer Reports published by Wiley Periodicals LLC.)
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- 2020
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23. Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic Breast Cancer by Hormone Receptor Status from SystHERs.
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Cobleigh M, Yardley DA, Brufsky AM, Rugo HS, Swain SM, Kaufman PA, Tripathy D, Hurvitz SA, O'Shaughnessy J, Mason G, Antao V, Li H, Chu L, and Jahanzeb M
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms, Male drug therapy, Breast Neoplasms, Male metabolism, Breast Neoplasms, Male pathology, Cohort Studies, Estrogen Receptor alpha metabolism, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Metastasis, Prospective Studies, Receptors, Progesterone metabolism, Registries, Survival Rate, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms mortality, Breast Neoplasms, Male mortality, Receptor, ErbB-2 metabolism
- Abstract
Purpose: We report treatments and outcomes in a contemporary patient population with HER2-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs)., Experimental Design: SystHERs (NCT01615068) was an observational, prospective registry study of U.S.-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes., Results: Of 977 eligible patients (enrolled from 2012 to 2016), 70.1% ( n = 685) had HR-positive and 29.9% ( n = 292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs 43.4 months; hazard ratio, 0.70; 95% confidence interval, 0.56-0.87). Compared with patients with high HR-positive staining (10%-100%, n = 550), those with low HR-positive staining (1%-9%, n = 60) received endocrine therapy less commonly (64.2% vs 33.3%) and had shorter median OS (53.8 vs 40.1 months). Similar median OS (43.4 vs 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%-9%)., Conclusions: Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%-9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%-100%)., (©2020 American Association for Cancer Research.)
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- 2020
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24. De Novo Versus Recurrent HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry.
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Tripathy D, Brufsky A, Cobleigh M, Jahanzeb M, Kaufman PA, Mason G, O'Shaughnessy J, Rugo HS, Swain SM, Yardley DA, Chu L, Li H, Antao V, and Hurvitz SA
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- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local drug therapy, Receptor, ErbB-2 genetics, Receptor, ErbB-2 therapeutic use, Registries, Trastuzumab therapeutic use, Treatment Outcome, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
Background: Limited data exist describing real-world treatment of de novo and recurrent HER2-positive metastatic breast cancer (MBC)., Materials and Methods: The Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012-2016), observational, prospective registry of patients with HER2-positive MBC. Patients aged ≥18 years and ≤6 months from HER2-positive MBC diagnosis were treated and assessed per their physician's standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression-free and overall survival (PFS and OS, by Kaplan-Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient-reported outcomes., Results: Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor-negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first-line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59-0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44-0.69; p < .0001)., Conclusion: Patients with de novo versus recurrent HER2-positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (clinicaltrials.gov)., Implications for Practice: SystHERs was an observational registry of patients with HER2-positive metastatic breast cancer (MBC), which is a large, modern, real-world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2-positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first-line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
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- 2020
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25. Influence of breast reconstruction on technical aspects of echocardiographic image acquisition compared with physician-assessed image quality.
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Duarte Ow J, Hemu M, Yakupovich A, Bhatt P, Gaddam H, Prabhu N, Fughhi I, Cobleigh M, Tracy M, Fogg L, and Okwuosa T
- Abstract
Introduction: Assessment of cardiac function after treatment for breast cancer relies on interval evaluation of ventricular function through echocardiography. Women who undergo mastectomy more frequently choose to undergo breast reconstruction with implant. This could impede assessment of cardiac function in those with left-sided implant. We aimed to examine whether left-sided breast reconstruction with tissue expanders (TE) affect echo image acquisition and quality, possibly affecting clinical decision-making., Methods: A retrospective case-control study was conducted in 190 female breast cancer patients who had undergone breast reconstruction with TE at an urban academic center. Echocardiographic technical assessment and image quality were respectively classified as excellent/good or adequate/technically difficult by technicians; and excellent/good or adequate/poor by 2 board-certified cardiologist readers. Likelihood ratio was used to test multivariate associations between image quality and left-sided TE., Results: We identified 32 women (81.3% white; mean age 48 years) with left-sided/bilateral TE, and 158 right-sided/no TE (76.6% white, mean age 57 years). In multivariable analyses, we found a statistically significant difference in technician-assessed difficulty in image acquisition between cases and controls ( p = 0.01); but no differences in physician-assessed image quality between cases and controls ( p = 0.09, Pearson's r = 0.467)., Conclusions: Left-sided breast TE appears to affect the technical difficulty of echo image acquisition, but not physician-assessed echo image quality. This likely means that echo technicians absorb most of the impediments associated with imaging patients with breast TE such that the presence of TE has no bearing on downstream clinical decision-making associated with echo image quality., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)
- Published
- 2019
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26. Somatic variants of potential clinical significance in the tumors of BRCA phenocopies.
- Author
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Buckingham L, Mitchell R, Maienschein-Cline M, Green S, Hu VH, Cobleigh M, Rotmensch J, Burgess K, and Usha L
- Abstract
Background: BRCA phenocopies are individuals with the same phenotype (i.e. cancer consistent with Hereditary Breast and Ovarian Cancer syndrome = HBOC) as their affected relatives, but not the same genotype as assessed by blood germline testing (i.e. they do not carry a germline BRCA1 or BRCA2 mutation). There is some evidence of increased risk for HBOC-related cancers in relatives of germline variant carriers even though they themselves test negative for the familial variant ( BRCA non-carriers). At this time, BRCA phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. This raises the question of whether the increased cancer risk in BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during BRCA analysis., Methods: To assess the nature and potential clinical significance of somatic variants in BRCA phenocopy tumors, DNA from BRCA non-carrier tumor tissue was analyzed using next generation sequencing of 572 cancer genes. Tumor diagnoses of the 11 subjects included breast, ovarian, endometrial and primary peritoneal carcinoma. Variants were called using FreeBayes genetic variant detector. Variants were annotated for effect on protein sequence, predicted function, and frequency in different populations from the 1000 genomes project, and presence in variant databases COSMIC and ClinVar using Annovar., Results: None of the familial BRCA1/2 mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were ROS1 (6/11 cases) and NUP98 (5/11 cases). BRCA2 somatic variants were found in 2/6 BRCA1 phenocopies, but 0/5 BRCA2 phenocopies. Variants of uncertain significance were found in other DNA repair genes ( ERCC1, ERCC3, ERCC4, FANCD2, PALB2 ), one mismatch repair gene ( PMS2 ), a DNA demethylation enzyme ( TET2 ), and two histone modifiers ( EZH2, SUZ12 )., Conclusions: Although limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in BRCA phenocopies., Competing Interests: Competing interestsThe authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
- Published
- 2019
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27. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.
- Author
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Hurvitz SA, O'Shaughnessy J, Mason G, Yardley DA, Jahanzeb M, Brufsky A, Rugo HS, Swain SM, Kaufman PA, Tripathy D, Chu L, Li H, Antao V, and Cobleigh M
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms etiology, Central Nervous System Neoplasms mortality, Central Nervous System Neoplasms therapy, Combined Modality Therapy, Disease Management, Female, Humans, Middle Aged, Odds Ratio, Patient Reported Outcome Measures, Prognosis, Prospective Studies, Survival Analysis, Treatment Outcome, Young Adult, Breast Neoplasms metabolism, Breast Neoplasms pathology, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms secondary, Receptor, ErbB-2 metabolism
- Abstract
Purpose: Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs)., Experimental Design: SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO)., Results: Among 977 eligible patients enrolled (2012-2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor-negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05-4.00 and HR 1.94; 95% CI, 1.52-2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment., Conclusions: Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice., (©2018 American Association for Cancer Research.)
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- 2019
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28. Can chimerism explain breast/ovarian cancers in BRCA non-carriers from BRCA-positive families?
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Mitchell R, Buckingham L, Cobleigh M, Rotmensch J, Burgess K, and Usha L
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- Adult, Aged, Female, Humans, Middle Aged, Mutation, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chimerism, Ovarian Neoplasms genetics
- Abstract
Hereditary breast and ovarian cancer syndrome (HBOC) is most frequently caused by mutations in BRCA1 or BRCA2 (in short, BRCA) genes. The incidence of hereditary breast and ovarian cancer in relatives of BRCA mutation carriers who test negative for the familial mutation (non-carriers) may be increased. However, the data is controversial, and at this time, these individuals are recommended the same cancer surveillance as general population. One possible explanation for BRCA phenocopies (close relatives of BRCA carriers who have developed cancer consistent with HBOC but tested negative for a familial mutation) is natural chimerism where lack of detectable mutation in blood may not rule out the presence of the mutation in the other tissues. To test this hypothesis, archival tumor tissue from eleven BRCA phenocopies was investigated. DNA from the tumor tissue was analyzed using sequence-specific PCR, capillary electrophoresis, and pyrosequencing. The familial mutations were originally detected in the patients' first-degree relatives by commercial testing. The same testing detected no mutations in the blood of the patients under study. The test methods targeted only the known familial mutation in the tumor tissue. Tumor diagnoses included breast, ovarian, endometrial and primary peritoneal carcinoma. None of the familial mutations were found in the tumor samples tested. These results do not support, but do not completely exclude, the possibility of chimerism in these patients. Further studies with comprehensive sequence analysis in a larger patient group are warranted as a chimeric state would further refine the predictive value of genetic testing to include BRCA phenocopies.
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- 2018
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29. Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.
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Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer E, Naughton M, Goetz MP, Russell C, Tripathy D, Cobleigh M, Forero A, Pluard TJ, Anders C, Niravath PA, Thomas S, Anderson J, Bumb C, Banks KC, Lanman RB, Bryce R, Lalani AS, Pfeifer J, Hayes DF, Pegram M, Blackwell K, Bedard PL, Al-Kateb H, and Ellis MJC
- Subjects
- Adult, Aged, Breast Neoplasms genetics, Breast Neoplasms pathology, Disease-Free Survival, Female, Humans, Middle Aged, Mutation, Neoplasm Metastasis, Quinolines adverse effects, Treatment Outcome, Breast Neoplasms drug therapy, Circulating Tumor DNA genetics, Quinolines administration & dosage, Receptor, ErbB-2 genetics
- Abstract
Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2
mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut ). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut , nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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30. Growth of human squamous head and neck cancer in vitro.
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Cobleigh MA, Gallagher PA, Hill JH, Applebaum EL, and McGuire WP
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- Cell Separation, Cells, Cultured, Cytological Techniques, Female, Humans, Ovarian Neoplasms pathology, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms pathology
- Abstract
This study was undertaken to define the cloning efficiency of squamous head and neck (H/N) cancer in soft agar. Twenty squamous cell carcinomas of H/N origin were mechanically dissociated and cultured in the human tumor clonogenic assay ( HTSCA ). No growth was observed. Nine ascites specimens from separate patients with ovarian cancer were cultured during the same time period, and six grew, all with more than 30 colonies per plate. Thirty-one additional H/N specimens were enzymatically dissociated and cultured in the HTSCA . Again, no growth was observed. Sixteen of these enzymatically dissociated specimens were simultaneously cultured in identical media without agar. Five specimens grew. We conclude that squamous carcinoma of H/N requires anchorage and fibroblast support for successful growth in culture. Suspension in semisolid media is less effective than liquid tissue culture systems for in vitro growth of this tumor type.
- Published
- 1984
31. Culture of squamous head and neck cancer on 3T3 fibroblasts following isokinetic velocity sedimentation.
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Cobleigh MA, Kennedy JL, Hill JH, Lindholm KM, Langenberg PW, and Applebaum EL
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- Cell Count, Cell Survival, Cells, Cultured, Centrifugation, Density Gradient, Fibroblasts pathology, Humans, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms pathology
- Abstract
Growth in culture of squamous head and neck cancer is hampered by microbial contamination, low plating efficiency, and cellular heterogeneity within tumors. Furthermore, clumps of cells must be removed if plating efficiency is to be accurately determined. Isokinetic velocity sedimentation was applied to 44 primary tumor specimens in an effort to minimize these problems. Seven fractions were evaluated for cell number, clump number, cell viability, clonogenic growth, plating efficiency, and microbial overgrowth. Unseparated specimens were simultaneously cultured. Microbial growth was significantly associated with the highest gradient fraction. Clumps were significantly associated with the lowest gradient fraction. Colony formation was significantly associated with middle gradient isokinetic velocity sedimentation, although seven specimens grew only when fractionated, suggesting the possibility of inhibitor cells within the tumor specimen.
- Published
- 1986
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