405 results on '"Budd, G. Thomas"'
Search Results
152. Adenoid cystic carcinoma of the salivary gland: Sustained complete response to chemotherapy
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Budd, G. Thomas, primary and Groppe, C. W., additional
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- 1983
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153. Therapeutic Trial Of Prostacyclin In Thrombotic Thrombocytopenic Purpura (TTP)
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Budd, G Thomas, additional, Bukowski, Ronald M, additional, Lucas, Fred V, additional, Cook, Linda F, additional, and Cocchetto, David M, additional
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- 1981
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154. Supplement Use and Chemotherapy-Induced Peripheral Neuropathy in a Cooperative Group Trial (S0221): The DELCaP Study.
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Zirpoli, Gary R, McCann, Susan E, Sucheston-Campbell, Lara E, Hershman, Dawn L, Ciupak, Gregory, Davis, Warren, Unger, Joseph M, Moore, Halle C F, Stewart, James A, Isaacs, Claudine, Hobday, Timothy J, Salim, Muhammad, Hortobagyi, Gabriel N, Gralow, Julie R, Budd, G Thomas, Albain, Kathy S, and Ambrosone, Christine B
- Abstract
Background: Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN.Methods: At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses.Results: Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN.Conclusions: Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted. [ABSTRACT FROM AUTHOR]- Published
- 2017
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155. A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.
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Marotta, Michael, Chen, Xiongfong, Inoshita, Ayako, Stephens, Robert, Thomas Budd, G, Crowe, Joseph P, Lyons, Joanne, Kondratova, Anna, Tubbs, Raymond, Tanaka, Hisashi, and Budd, G Thomas
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BREAST cancer research ,HUMAN genome ,HER2 protein ,POLYMERASE chain reaction ,GENE amplification - Abstract
Introduction: Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems.Methods: We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint.Results: We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution.Conclusions: Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification. [ABSTRACT FROM AUTHOR]- Published
- 2012
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156. Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer.
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Cristofanilli, Massimo, Budd, G. Thomas, Ellis, Matthew J., Stopeck, Alison, Matera, Jeri, Miller, M. Craig, Reuben, James M., Doyle, Gerald V., Allard, W. Jeffrey, Terstappen, Leon W.M.M., and Hayes, Daniel F.
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CANCER cell proliferation , *BREAST cancer prognosis , *MORTALITY , *TUMORS , *CANCER treatment , *CLINICAL trials , *HEALTH outcome assessment - Abstract
Background: We tested the hypothesis that the level of circulating tumor cells can predict survival in metastatic breast cancer. Methods: In a prospective, multicenter study, we tested 177 patients with measurable metastatic breast cancer for levels of circulating tumor cells both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. Results: Outcomes were assessed according to levels of circulating tumor cells at baseline, before the patients started a new treatment for metastatic disease. Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy. The multivariate Cox proportional-hazards regression showed that, of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. Conclusions: The number of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer. N Engl J Med 2004;351:781-91. [ABSTRACT FROM AUTHOR]
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- 2004
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157. Impact of early detection on cancer curability: A modified Delphi panel study.
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Schwartzberg, Lee, Broder, Michael S., Ailawadhi, Sikander, Beltran, Himisha, Blakely, L. Johnetta, Budd, G. Thomas, Carr, Laurie, Cecchini, Michael, Cobb, Patrick, Kansal, Anuraag, Kim, Ashley, Monk, Bradley J., Wong, Deborah J., Campos, Cynthia, and Yermilov, Irina
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EARLY detection of cancer , *PANEL analysis , *INTRAHEPATIC bile ducts , *BREAST , *MEDICAL screening , *BLOOD testing , *PANCREAS - Abstract
Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients. [ABSTRACT FROM AUTHOR]
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- 2022
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158. A randomised phase II trial of a trivalent ganglioside vaccine targeting GM2, GD2 and GD3 combined with immunological adjuvant OPT-821 versus OPT-821 alone in metastatic sarcoma patients rendered disease-free by surgery.
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Rosenbaum, Evan, Chugh, Rashmi, Ryan, Christopher W., Agulnik, Mark, Milhem, Mohammed M., George, Suzanne, Jones, Robin L., Chmielowski, Bartosz, Van Tine, Brian A., Tawbi, Hussein, Elias, Anthony D., Read, William L., Budd, G. Thomas, Qin, Li-Xuan, Rodler, Eve T., Hirman, Joe, Weiden, Paul, Bennett, Cathryn M., Livingston, Philip O., and Ragupathi, Govind
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IMMUNOMODULATORS , *METASTASIS , *CANCER vaccines , *SARCOMA - Published
- 2022
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159. Therapeutic Trial Of Prostacyclin In Thrombotic Thrombocytopenic Purpura (TTP)
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Budd, G Thomas, Bukowski, Ronald M, Lucas, Fred V, Cook, Linda F, and Cocchetto, David M
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- 1981
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160. Cardiac risk stratification in cancer patients: A longitudinal patient-patient network analysis.
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Hou, Yuan, Zhou, Yadi, Hussain, Muzna, Budd, G. Thomas, Tang, Wai Hong Wilson, Abraham, James, Xu, Bo, Shah, Chirag, Moudgil, Rohit, Popovic, Zoran, Watson, Chris, Cho, Leslie, Chung, Mina, Kanj, Mohamed, Kapadia, Samir, Griffin, Brian, Svensson, Lars, Collier, Patrick, and Cheng, Feixiong
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DISEASE risk factors , *CARDIOVASCULAR diseases , *CANCER patients , *STROKE , *CORONARY artery disease , *HEART failure , *CAUSES of death - Abstract
Background: Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records.Methods and Findings: We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p < 0.001; Troponin T > 0.05 μg/L versus Troponin T ≤ 0.01 μg/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings.Conclusions: In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology. [ABSTRACT FROM AUTHOR]- Published
- 2021
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161. POINT / COUNTER.
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Hudis, Clifford and Budd, G. Thomas
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DNA topoisomerase II , *BIOMARKERS - Abstract
The article presents contradictory opinions on whether topoisomerase II alpha is a valid biomarker for taxane sensitivity.
- Published
- 2009
162. Impact of Postmastectomy Radiation on Locoregional Recurrence in Breast Cancer Patients With 1-3 Positive Lymph Nodes Treated With Modern Systemic Therapy
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Tendulkar, Rahul D., Rehman, Sana, Shukla, Monica E., Reddy, Chandana A., Moore, Halle, Budd, G. Thomas, Dietz, Jill, Crowe, Joseph P., and Macklis, Roger
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MASTECTOMY , *CANCER radiotherapy , *CANCER relapse , *BREAST cancer treatment , *LYMPH nodes , *RETROSPECTIVE studies , *FOLLOW-up studies (Medicine) - Abstract
Purpose: Postmastectomy radiation therapy (PMRT) remains controversial for patients with 1-3 positive lymph nodes (LN+). Methods and Materials: We conducted a retrospective review of all 369 breast cancer patients with 1-3 LN+ who underwent mastectomy without neoadjuvant systemic therapy between 2000 and 2007 at Cleveland Clinic. Results: We identified 271 patients with 1-3 LN+ who did not receive PMRT and 98 who did receive PMRT. The median follow-up time was 5.2 years, and the median number of LN dissected was 11. Of those not treated with PMRT, 79% received adjuvant chemotherapy (of whom 70% received a taxane), 79% received hormonal therapy, and 5% had no systemic therapy. Of the Her2/neu amplified tumors, 42% received trastuzumab. The 5-year rate of locoregional recurrence (LRR) was 8.9% without PMRT vs 0% with PMRT (P=.004). For patients who did not receive PMRT, univariate analysis showed 6 risk factors significantly (P<.05) correlated with LRR: estrogen receptor/progesterone receptor negative (hazard ratio [HR] 2.6), lymphovascular invasion (HR 2.4), 2-3 LN+ (HR 2.6), nodal ratio >25% (HR 2.7), extracapsular extension (ECE) (HR 3.7), and Bloom-Richardson grade III (HR 3.1). The 5-year LRR rate was 3.4% (95% confidence interval [CI], 0.1%-6.8%] for patients with 0-1 risk factor vs 14.6% [95% CI, 8.4%-20.9%] for patients with ≥2 risk factors (P=.0006), respectively. On multivariate analysis, ECE (HR 4.3, P=.0006) and grade III (HR 3.6, P=.004) remained significant risk factors for LRR. The 5-year LRR was 4.1% in patients with neither grade III nor ECE, 8.1% with either grade III or ECE, and 50.4% in patients with both grade III and ECE (P<.0001); the corresponding 5-year distant metastasis-free survival rates were 91.8%, 85.4%, and 59.1% (P=.0004), respectively. Conclusions: PMRT offers excellent control for patients with 1-3 LN+, with no locoregional failures to date. Patients with 1-3 LN+ who have grade III disease and/or ECE should be strongly considered for PMRT. [Copyright &y& Elsevier]
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- 2012
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163. Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.
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Chapman JW, Bayani J, SenGupta S, Bartlett JMS, Piper T, Quintayo MA, Virk S, Goss PE, Ingle JN, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Gelmon KA, Whelan TJ, Elliott C, Shepherd LE, Chen BE, and Taylor KJ
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- Humans, Female, Middle Aged, Aged, Canada, Chemotherapy, Adjuvant, Disease-Free Survival, Anastrozole therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms mortality, Receptors, Progesterone metabolism, Receptors, Progesterone analysis, Receptors, Estrogen metabolism, Receptors, Estrogen analysis, Postmenopause, Androstadienes therapeutic use, Androstadienes administration & dosage
- Abstract
Purpose: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes., Methods: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05., Results: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS ( P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated ( P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS ( P = .001) in models with ER., Conclusion: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.
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- 2024
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164. Neoadjuvant Reirradiation for Radiation Therapy-Associated Angiosarcoma of the Breast.
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Asha W, Al-Hilli Z, Djohan R, Budd GT, Obi E, Fleming-Hall E, Yang K, Grobmyer S, Cherian S, Tendulkar R, and Shah C
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- Humans, Female, Middle Aged, Aged, Neoplasms, Radiation-Induced etiology, Adult, Dose Fractionation, Radiation, Retrospective Studies, Hemangiosarcoma etiology, Hemangiosarcoma radiotherapy, Breast Neoplasms radiotherapy, Breast Neoplasms pathology, Re-Irradiation adverse effects, Neoadjuvant Therapy adverse effects
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Purpose: Radiation-associated angiosarcoma of the breast (RAASB) is a rare side effect after breast radiation and has been associated with poor outcomes. At this time, there is no consensus regarding management of RAASB, and the role of reirradiation remains controversial. We present our modern institutional outcomes in managing RAASB with incorporation of neoadjuvant hyperfractionated reirradiation., Methods and Materials: Patients identified were treated between 2016 and 2020 with inclusion of any histologically proven RAASB without metastatic disease at diagnosis, while excluding those with a history of radiation therapy outside of the breast/chest wall or other sarcoma histologies. Major wound complications were defined as requiring wound care and/or wound vacuum or return to the operating room for wound repair at any time after surgery., Results: Eight patients were identified, and the median follow-up was 34 months. Median time to RAASB development was 8 years from initial radiation therapy. With respect to RAASB management, all underwent surgery and neoadjuvant reirradiation therapy, and all but 1 patient received taxol-based chemotherapy. At last follow-up, 7 patients remained free of disease, and 1 patient died with distant disease. With respect to acute toxicity after reirradiation, all patients developed at least acute grade 2 toxicities. Five of the 8 patients developed a major wound complication., Conclusions: Our institutional analysis suggests excellent local control and survival outcomes for RAASB treated with neoadjuvant hyperfractionated reirradiation, surgery, and taxol-based chemotherapy. However, major wound complications represent a major challenge with this approach. Future studies should consider how best to improve the therapeutic ratio while maintaining high rates of local control and survival., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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165. Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.
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Chen CS, Zirpoli G, Budd GT, Barlow WE, Pusztai L, Hortobagyi GN, Albain KS, Godwin AK, Thompson A, Henry NL, Ambrosone CB, Stringer KA, and Hertz DL
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Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity., Methods: Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm., Results: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality., Conclusions: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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166. Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer.
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Wilkerson AD, Parthasarathy PB, Stabellini N, Mitchell C, Pavicic PG Jr, Fu P, Rupani A, Husic H, Rayman PA, Swaidani S, Abraham J, Budd GT, Moore H, Al-Hilli Z, Ko JS, Baar J, Chan TA, Alban T, Diaz-Montero CM, and Montero AJ
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- Humans, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Gene Expression Profiling, Progression-Free Survival, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Purpose: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy., Patients and Methods: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan-Meier method. Bulk RNA sequencing was employed for correlative studies., Results: Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months [95% confidence interval (CI), 4-8.5 months]. For patients with CR, DOR was >24 months. Overall median PFS and OS were 5.8 (95% CI, 4.7-8.5 months) and 13.4 months (8.9-17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved OS (P = 0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy., Conclusions: Pretreatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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167. Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221.
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Chen CS, Zirpoli G, Barlow WE, Budd GT, McKiver B, Pusztai L, Hortobagyi GN, Albain KS, Damaj MI, Godwin AK, Thompson A, Henry NL, Ambrosone CB, Stringer KA, and Hertz DL
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- Humans, Female, Animals, Mice, Paclitaxel adverse effects, Prospective Studies, Vitamin D therapeutic use, Risk Factors, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases epidemiology, Breast Neoplasms complications, Breast Neoplasms drug therapy, Vitamin D Deficiency complications, Vitamin D Deficiency epidemiology, Antineoplastic Agents therapeutic use
- Abstract
Background: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor., Methods: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet., Results: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05)., Conclusions: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.
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- 2023
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168. Stereotactic Body Radiation Therapy for Sarcoma Pulmonary Metastases.
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Asha W, Koro S, Mayo Z, Yang K, Halima A, Scott J, Scarborough J, Campbell SR, Budd GT, Shepard D, Stephans K, Videtic GM, and Shah C
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- Humans, Dose Fractionation, Radiation, Retrospective Studies, Radiosurgery methods, Lung Neoplasms, Sarcoma pathology
- Abstract
Background: Lung metastases are the most common form of distant failure for patients diagnosed with sarcoma with metastasectomy considered for some patients with limited metastatic disease and good performance status. Alternatives to surgery such as stereotactic body radiation therapy (SBRT) can be considered, though data are limited. We present outcomes after SBRT for sarcoma lung metastases., Methods: Fifty sarcoma patients with 109 lung metastases were treated with SBRT between 2005 and 2021. Outcomes evaluated included local control (LC), overall survival (OS), and toxicity including lung pneumonitis/fibrosis, chest wall toxicity, dermatitis, brachial plexus, and esophageal toxicity. Systemic therapy receipt before and after SBRT was recorded., Results: SBRT schedules were divided into 3 cohorts: 30 to 34 Gy/1fx (n=10 [20%]), 48 to 50 Gy/4 to 5fx (n=24[48%]), and 60 Gy/5fx (n=16[32%]). With a median follow-up of 19.5 months, 1/3-year LC rates were 96%/88% and 1/3-year OS 77%/50%, respectively. There was no differences between the 3 regimens in terms of LC, OS, or toxicity. Size >4 cm was a predictor of worse LC ( P =0.031) and worse OS ( P = 0.039) on univariate analysis. The primary pattern of failure was new metastases (64%) of which the majority were in the contralateral lung (52%). One-year chemotherapy-free survival was 85%. Overall, 76% of patients did not require chemotherapy initiation or change of chemotherapy regimen after lung SBRT. Toxicity was reported in 16% of patients overall, including 25%, 20%, and 14% in the 30 to 34 Gy/1fx, 48 to 50 Gy/4 to 5fx, and 60 Gy/5fx cohorts, respectively., Conclusions: SBRT outcomes for lung metastases from sarcoma demonstrate high rates of LC and are similar with different dose/fractionation regimens. Lung SBRT is associated with prolonged chemotherapy-free survival. Prospective validation of these results is warranted., Competing Interests: C.S.: Consultant ImpediMed, Consultant PreludeDX, Consultant Videra Surgical, Grants—Varian Medical Systems, VisionRT, PreludeDx. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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169. Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.
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Johnson KB, Sharma A, Henry NL, Wei M, Bie B, Hershberger CE, Rhoades EE, Sen A, Johnson RE, Steenblik J, Hockings J, Budd GT, Eng C, Foss J, and Rotroff DM
- Abstract
Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gap s in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN., Competing Interests: DMR has received research funding from Novo Nordisk, has an equity stake in Clarified Precision Medicine, and has intellectual property related to treatment decision making in the context of type 2 diabetes and liver cancer. No other potential conflicts of interest relevant to this article were reported. The remaining 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., (© 2023 Johnson, Sharma, Henry, Wei, Bie, Hershberger, Rhoades, Sen, Johnson, Steenblik, Hockings, Budd, Eng, Foss and Rotroff.)
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- 2023
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170. Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer.
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Cannioto RA, Attwood KM, Davis EW, Mendicino LA, Hutson A, Zirpoli GR, Tang L, Nair NM, Barlow W, Hershman DL, Unger JM, Moore HCF, Isaacs C, Hobday TJ, Hortobagyi GN, Gralow JR, Albain KS, Budd GT, and Ambrosone CB
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- Humans, Female, United States, Middle Aged, Prospective Studies, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local prevention & control, Life Style, Hormones, Breast Neoplasms epidemiology, Breast Neoplasms prevention & control
- Abstract
Importance: The American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown., Objective: To investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality., Design, Setting, and Participants: The Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor-negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023., Exposure: An aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle., Main Outcomes and Measures: Disease recurrence and all-cause mortality., Results: A total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59)., Conclusions and Relevance: In this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.
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- 2023
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171. Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors.
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Mo H, Renna CE, Moore HCF, Abraham J, Kruse ML, Montero AJ, LeGrand SB, Wang L, and Budd GT
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- Adolescent, Adult, Aged, Breast Neoplasms pathology, Female, Humans, Middle Aged, Quality of Life, Receptor, ErbB-2 drug effects, Retrospective Studies, Treatment Outcome, Androstadienes therapeutic use, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Everolimus therapeutic use, Receptor, ErbB-2 metabolism
- Abstract
Purpose: Everolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors., Methods: A retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety., Results: 192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different., Conclusion: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
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172. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).
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Wagner MJ, Othus M, Patel SP, Ryan C, Sangal A, Powers B, Budd GT, Victor AI, Hsueh CT, Chugh R, Nair S, Leu KM, Agulnik M, Sharon E, Mayerson E, Plets M, Blanke C, Streicher H, Chae YK, and Kurzrock R
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Hemangiosarcoma pathology, Humans, Immune Checkpoint Inhibitors administration & dosage, Ipilimumab administration & dosage, Male, Middle Aged, Neoplasm Metastasis, Nivolumab administration & dosage, Prospective Studies, Rare Diseases pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, CTLA-4 Antigen antagonists & inhibitors, Hemangiosarcoma drug therapy, Rare Diseases drug therapy
- Abstract
Purpose: Angiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study., Methods: This is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used., Results: Overall, there were 16 evaluable patients. Median age was 68 years (range, 25-81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3-4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR., Conclusion: The combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma., Trial Registration Number: NCT02834013., Competing Interests: Competing interests: MJW reports scientific advisory income from Adaptimmune and Deciphera. His university received research funding from Athenex, Adaptimmune, Deciphera, GlaxoSmithKline, Incyte, InhibRX. MO reports consulting with Merck, Daiichi Sankyo, Biosight and is on a data safety monitoring board for Celgene and GlycomimeticsSP reports scientific advisory income from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Illumina, Merck, Rakuten, Paradigm, Tempus. Patel’s university receives research funding from Bristol-Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, IovanceCR reports consulting from AstraZeneca, Bristol-Meyer Squibb, Deciphera, Eisai, Exelixis, Janssen. Ryan’s institution received research funding from Bristol-Myers Squibb, Daiichi-Sankyo, Exelixis, Genetech, GlaxoSmithKline/Novartis, Karyopharm Therapeutics, Leducq, Merck, Nektar, Pfizer, and Xynomic. GTB reports honoraria for consulting and speaking from Deciphera. His institution received research support from Ambrx, Roche, Daiichi, TraconAV reports consulting from Foundation medicine and case roundtable for Sanofi. CR reports personal fees from Epizyme, Ipsen, Deciphera; travel/non-financial support from Janssen, Astra Zeneca, Springworks, GSK; Research funding to institution from Plexxicon, AADi, Novartis, Medivation, Advenchen, Epizyme, Springworks, Mundipharma, GSK, Qilu Puget Sound.MA reports consulting or Advisory role with Lilly, Adaptimmune, Regeneron, and AstraZeneca; speakers bureau with Bristol-Myers Squib, Bayer, and Deciphera. His institution received research funding from Exelixis. YKC reports research grants from AbbVie, Bristol‐Myers Squibb, Biodesix, Lexent Bio, and Freenome and consulting fees, payments, and/or honoraria from Roche/Genentech, AstraZeneca, Bristol‐Myers Squibb, Foundation Medicine, Counsyl, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Pfizer, Tempus, Lunit, and Takeda. RK reports consultant and/or speaker fees and/or advisory board for Actuate Therapeutics, Bicara Therapeutics, Biological Dynamics, Neomed, Pfizer, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a cofounder of CureMatch. Her institution receives research funding RK research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance.The other authors made no disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
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- 2021
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173. Temporal Trends of Cardiac Outcomes and Impact on Survival in Patients With Cancer.
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Hussain M, Hou Y, Watson C, Moudgil R, Shah C, Abraham J, Budd GT, Tang WHW, Finet JE, James K, Estep JD, Xu B, Hu B, Cremer P, Jellis C, Grimm RA, Greenberg N, Popovic ZB, Cho L, Desai MY, Nissen SE, Kapadia SR, Svensson LG, Griffin BP, Cheng F, and Collier P
- Subjects
- Aged, Female, Follow-Up Studies, Heart Diseases epidemiology, Humans, Incidence, Male, Middle Aged, Neoplasms complications, Ohio epidemiology, Retrospective Studies, Risk Factors, Survival Rate trends, Heart Diseases complications, Neoplasms mortality
- Abstract
To evaluate the temporal relations of cardiovascular disease in oncology patients referred to cardio-oncology and describe the impact of cardiovascular disease and cardiovascular risk factors on outcomes. All adult oncology patients referred to the cardio-oncology service at the Cleveland Clinic from January 2011 to June 2018 were included in the study. Comprehensive clinical information were collected. The impact on survival of temporal trends of cardiovascular disease in oncology patients were assessed with a Cox proportional hazards model and time-varying covariate adjustment for confounders. In total, 6,754 patients were included in the study (median age, 57 years; [interquartile range, 47 to 65 years]; 3,898 women [58%]; oncology history [60% - breast cancer, lymphoma, and leukemia]). Mortality and diagnosis of clinical cardiac disease peaked around the time of chemotherapy. 2,293 patients (34%) were diagnosed with a new cardiovascular risk factor after chemotherapy, over half of which were identified in the first year after cancer diagnosis. Patients with preexisting and post-chemotherapy cardiovascular disease had significantly worse outcomes than patients that did not develop any cardiovascular disease (p < 0.0001). The highest 1-year hazard ratios (HR) of post-chemotherapy cardiovascular disease were significantly associated with male (HR 1.81; 95% confidence interval 1.55 to 2.11; p < 0.001] and diabetes [HR 1.51; 95% confidence interval 1.26 to 1.81; p < 0.001]. In conclusion, patients referred to cardio-oncology, first diagnosis of cardiac events peaked around the time of chemotherapy. Those with preexisting or post-chemotherapy cardiovascular disease had worse survival. In addition to a high rate of cardiovascular risk factors at baseline, risk factor profile worsened over course of follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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174. Impact of timing of atrial fibrillation, CHA 2 DS 2 -VASc score and cancer therapeutics on mortality in oncology patients.
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Hussain M, Misbah R, Donnellan E, Alkharabsheh S, Hou Y, Cheng F, Crookshanks M, Watson CJ, Toth AJ, Houghtaling P, Moudgil R, Budd GT, Tang WHW, Kwon DH, Jaber W, Griffin B, Kanj M, and Collier P
- Subjects
- Aged, Atrial Fibrillation complications, Follow-Up Studies, Humans, Middle Aged, Neoplasms complications, Predictive Value of Tests, Prognosis, Retrospective Studies, Risk Factors, Time Factors, Atrial Fibrillation diagnosis, Neoplasms diagnosis, Propensity Score, Risk Assessment methods
- Abstract
Objectives: To investigate timing and age distribution of atrial fibrillation (AF) in selected oncology patients, and the impact of AF timing, CHA
2 DS2 -VASc score and cancer therapeutics on mortality., Methods: This is a retrospective cohort study of oncology patients referred to the cardio-oncology service from 2011 to 2018 for echocardiographic cardiosurveillance and/or pre-existing cardiovascular risk factor/disease management. Rates of first AF diagnosis was assessed using a parametric multiphase hazard model (predictive modelling) and non-parametrically by Kaplan-Meier with transformations tested using a bootstrap methodology., Results: Among 6754 patients identified, 174 patients had their first AF diagnosis before cancer while 609 patients had their first diagnosis of AF after cancer. Most first AF diagnosis occurred at/early after cancer diagnosis. Increasing AF prevalence at time of cancer diagnosis was seen across older age groups ranges. Diagnosis of cancer at an older age and exposure to cardiotoxic treatment (anthracyclines, HER2-neu inhibitors, tyrosine kinase inhibitors including ibrutinib and radiation) were associated with an increased risk of AF.Modelling of the hazard function of AF identified a high left-skewed peak within 3 years after cancer diagnosis ('early phase'), followed by a gradual late slight rise 3 years after cancer diagnosis ('late phase'). AF diagnosis was only associated with death in the early phase (p<0.001), while CHA2 DS2 -VASc score was only associated with death in the late phase (p<0.001)., Conclusions: This study reports a nuanced/complex relationship between AF and cancer. First diagnosis of AF in patients with cancer was more common at/early after cancer diagnosis, especially in older patients and those exposed to cardiotoxic treatment. Pre-existing AF or a diagnosis of AF within 3 years after cancer diagnosis carried a negative prognosis. CHA2 DS2 -VASc score did not relate to mortality in those that developed AF within 3 years of cancer diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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175. Incidence and outcomes of cutaneous angiosarcoma: A SEER population-based study.
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Conic RRZ, Damiani G, Frigerio A, Tsai S, Bragazzi NL, Chu TW, Mesinkovska NA, Koyfman SA, Joshi NP, Budd GT, Vidimos A, and Gastman BR
- Subjects
- Age Factors, Aged, Aged, 80 and over, Chemoradiotherapy, Adjuvant statistics & numerical data, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant statistics & numerical data, Dermatologic Surgical Procedures statistics & numerical data, Female, Hemangiosarcoma therapy, Humans, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Neoadjuvant Therapy methods, Neoadjuvant Therapy statistics & numerical data, Neoplasms, Second Primary therapy, Prognosis, Retrospective Studies, Risk Factors, SEER Program statistics & numerical data, Skin Neoplasms therapy, Survival Rate, United States epidemiology, Hemangiosarcoma epidemiology, Neoplasms, Second Primary epidemiology, Skin Neoplasms epidemiology
- Abstract
Background: Cutaneous angiosarcoma (CAS) is a rare, malignant tumor of vascular mesenchymal origin accounting for less than 1% of all sarcomas., Objective: To examine epidemiologic trends and outcomes in CAS., Methods: In this retrospective, population-based study, patients with CAS were identified from the Surveillance Epidemiology and End Results database. Age, sex, and race-standardized incidence rates (IRs) were calculated. Survival was assessed with Kaplan-Meier curves and Cox proportional hazards models., Results: Of 811 patients with CAS, 43% had a prior primary cancer. CAS IR for patients without prior primary cancers dropped from 5.88 per 100,000 in 1973 to 1984 to 2.87 per 100,000 in 2005 to 2014. In those with prior primary cancers, IR rose from 0.03 per 100,000 in 1973 to 1984 to 2.25 per 100,000 in 2005 to 2014. On multivariate analysis, patients older than 70 years of age had a higher risk of death compared with those younger than 50 years (hazard ratio, 2.16; 95% confidence interval 1.33-3.57; P = .002), and distant disease was associated with increased risk of death compared with localized disease (hazard ratio, 1.50; 95% confidence interval, 1.11-2.03; P = .008). Receipt of surgery and/or radiation therapy was not associated with survival., Limitations: Potential selection and miscoding bias, retrospective nature., Conclusion: CAS rates are rising among those with other prior primary cancers. Survival is not affected by current therapeutic strategies, highlighting the need for additional treatment options., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2020
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176. Can CDK4/6 inhibitors cause fatal lung injury?
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Jazieh KA, Budd GT, Dalpiaz N, and Abraham J
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- Aminopyridines administration & dosage, Aminopyridines adverse effects, Aminopyridines pharmacology, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles pharmacology, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Humans, Piperazines administration & dosage, Piperazines adverse effects, Piperazines pharmacology, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Purines administration & dosage, Purines adverse effects, Purines pharmacology, Pyridines administration & dosage, Pyridines adverse effects, Pyridines pharmacology, Antineoplastic Agents adverse effects, Lung Diseases chemically induced, Protein Kinase Inhibitors adverse effects
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- 2019
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177. LATE-ONSET CHOROIDAL METASTASIS FROM BREAST CANCER.
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Levison AL, Erenler F, Zhao Y, Martin DF, Lowder C, Budd GT, and Singh AD
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- Age of Onset, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Aromatase Inhibitors therapeutic use, Choroid Neoplasms pathology, Female, Humans, Treatment Outcome, Breast Neoplasms pathology, Choroid Neoplasms secondary
- Abstract
Purpose: Report occurrence of late-onset choroidal metastasis from breast cancer., Methods: Retrospective chart review., Results: The authors report 3 patients with choroidal metastasis from breast cancer that presented more than 20 years after diagnosis of the primary tumor. The choroidal metastases were the presenting feature of metastatic disease in all three patients, but after imaging, all patients had metastasis elsewhere as well. Two of the patients' tumors were known, ER+, and the hormone receptor status of the third patient was unknown. All three patients were treated with aromatase inhibitors with good response., Conclusion: Late onset of metastatic disease, an excellent response to hormonal therapy, and a prolonged survival despite presence of systemic disease suggests a milder variant within the broad category of breast cancer patients with uveal metastases. Awareness of this entity can minimize the risk of misdiagnosis and avoid potentially toxic local therapy.
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- 2018
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178. Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.
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Sucheston-Campbell LE, Clay-Gilmour AI, Barlow WE, Budd GT, Stram DO, Haiman CA, Sheng X, Yan L, Zirpoli G, Yao S, Jiang C, Owzar K, Hershman D, Albain KS, Hayes DF, Moore HC, Hobday TJ, Stewart JA, Rizvi A, Isaacs C, Salim M, Gralow JR, Hortobagyi GN, Livingston RB, Kroetz DL, and Ambrosone CB
- Subjects
- Black or African American genetics, Breast Neoplasms complications, Breast Neoplasms genetics, Breast Neoplasms pathology, Bridged-Ring Compounds therapeutic use, Female, Genome-Wide Association Study, Genomics, Genotype, Humans, Peripheral Nervous System Diseases pathology, Polymorphism, Single Nucleotide, Taxoids therapeutic use, White People genetics, Breast Neoplasms drug therapy, Bridged-Ring Compounds adverse effects, Genetic Predisposition to Disease, Peripheral Nervous System Diseases genetics, Taxoids adverse effects
- Abstract
Objective: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN., Patients and Methods: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus
- Published
- 2018
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179. Supplement Use and Chemotherapy-Induced Peripheral Neuropathy in a Cooperative Group Trial (S0221): The DELCaP Study.
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Zirpoli GR, McCann SE, Sucheston-Campbell LE, Hershman DL, Ciupak G, Davis W, Unger JM, Moore HCF, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Budd GT, Albain KS, and Ambrosone CB
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- Adult, Clinical Trials, Phase III as Topic, Cohort Studies, Female, Humans, Middle Aged, Peripheral Nervous System Diseases chemically induced, Prognosis, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Dietary Supplements, Exercise, Life Style, Peripheral Nervous System Diseases prevention & control, Quality of Life
- Abstract
Background: Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN., Methods: At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses., Results: Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN., Conclusions: Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted.
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- 2017
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180. Symptoms, Quality of Life, and Daily Activities in People With Newly Diagnosed Solid Tumors Presenting to a Medical Oncologist.
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Thomas S, Walsh D, Shrotriya S, Aktas A, Hullihen B, Estfan B, Budd GT, Hjermstad MJ, and O'Connor B
- Subjects
- Aged, Anxiety epidemiology, Anxiety etiology, Fatigue epidemiology, Fatigue etiology, Female, Humans, Male, Medical Oncology statistics & numerical data, Neoplasms diagnosis, Neoplasms pathology, Pain epidemiology, Pain etiology, Prospective Studies, Activities of Daily Living psychology, Neoplasms psychology, Quality of Life psychology
- Abstract
Introduction: Symptom and Quality of Life (QOL) data are important patient reported outcomes. Early identification of these is critical for appropriate interventions. Data collection may be helped by modern information technology., Aim: This study examined symptoms and QOL in people with solid tumors at their first visit to a medical oncologist. We also evaluated the clinical utility of tablet computers (TC) to collect this data., Methods: This was a prospective study of 105 consecutive patients in the cancer outpatient clinic of a tertiary level academic medical center. Symptom and QOL data was collected by TC with wireless database upload., Results: One-third participants had moderate to severe pain; almost half clinically significant pain that interfered with daily activities. Tiredness, anxiety, and drowsiness were common (prevalence - 79%, 63% and 50% respectively). One-third of those who had items identified from the Edmonton System Assessment System also volunteered other symptoms, mostly gastrointestinal problems. Many of those affected also reported impaired Global Wellbeing and low Overall QOL. There was a 98% completion rate, which took on average ten minutes. Direct observation and informal feedback from patients and physicians regarding the acceptability of TC in this setting was uniformly positive., Conclusions: Amongst people with newly diagnosed solid tumors clinically important psychological and physical symptoms, QOL problems and difficulties with daily activities were commonly present in the 24-hour period and in the week before a first Medical Oncology visit. Symptom and QOL data collection by TC in busy outpatient clinics showed good clinical utility.
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- 2017
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181. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).
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Ellis MJ, Suman VJ, Hoog J, Goncalves R, Sanati S, Creighton CJ, DeSchryver K, Crouch E, Brink A, Watson M, Luo J, Tao Y, Barnes M, Dowsett M, Budd GT, Winer E, Silverman P, Esserman L, Carey L, Ma CX, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther JM, Dayao Z, Ota D, Leitch M, Olson JA Jr, Allred DC, and Hunt K
- Subjects
- Aged, Anastrozole, Androstadienes therapeutic use, Breast Neoplasms pathology, Breast Neoplasms surgery, Clinical Decision-Making, Female, Follow-Up Studies, Humans, Ki-67 Antigen genetics, Letrozole, Middle Aged, Mitotic Index, Neoadjuvant Therapy methods, Neoplasm Metastasis, Neoplasm Staging, Nitriles therapeutic use, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Receptors, Estrogen analysis, Receptors, Estrogen genetics, Receptors, Progesterone genetics, Survival Rate, Transcriptome, Triazoles therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Aromatase Inhibitors therapeutic use, Breast Neoplasms chemistry, Breast Neoplasms drug therapy, Ki-67 Antigen analysis, Neoplasm Recurrence, Local
- Abstract
Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).
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- 2017
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182. Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer.
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Tiwari SR, Mishra P, Raska P, Calhoun B, Abraham J, Moore H, Budd GT, Fanning A, Valente S, Stewart R, Grobmyer SR, and Montero AJ
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- Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms metabolism, Carboplatin administration & dosage, Carboplatin adverse effects, Disease-Free Survival, Docetaxel, Female, Humans, Middle Aged, Neoadjuvant Therapy adverse effects, Registries, Retrospective Studies, Survival Analysis, Taxoids administration & dosage, Taxoids adverse effects, Trastuzumab administration & dosage, Trastuzumab adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms drug therapy, Neoadjuvant Therapy methods, Receptor, ErbB-2 metabolism
- Abstract
Background: Pertuzumab is FDA approved in the preoperative setting in combination with trastuzumab and chemotherapy, in women with nonmetastatic HER2 + breast cancer. The TRYPHAENA trial (n = 77) reported a pathologic complete response rate (pCR), i.e., ypT0ypN0, of 52 % in patients treated with neoadjuvant (docetaxel, carboplatin, trastuzumab, & pertuzumab) TCH-P. Aside from this study, there is limited information regarding the safety and efficacy of TCH-P in the neoadjuvant setting. Our goal was to evaluate the safety and efficacy of neoadjuvant TCH-P in a non-clinical trial setting., Materials and Methods: Cancer data registry was utilized to identify patients with HER2 + nonmetastatic breast cancer that received neoadjuvant TCH-P. pCR was defined as the absence of invasive or noninvasive cancer in breast and lymph nodes, i.e., ypT0ypN0., Results: 70 patients with a median age of 52 years met our inclusion criteria. Clinical staging was I-8.5 %; II-68.5 %; and III-22.8 %. 60 % of patients had hormone receptor (HR)-positive tumors. 23 % (16/71) of patients required dose reduction for rash, diarrhea, neuropathy, or thrombocytopenia. Overall, no patients developed grade 3-4 left ventricular systolic dysfunction(LVSD); an asymptomatic reduction in LVEF of >10 % was observed in three patients. The overall observed pCR rate was 53 %. As expected, the pCR rate was higher in patients with HR-negative breast cancer than for patients with HR+ disease: 69 % (20/29) vs. 42 % (17/41), respectively. The axillary downstaging rate was approximately 53 % (19/36)., Conclusion: Neoadjuvant TCH-P, in a nonclinical trial setting, was associated with a pCR rate of 53 % similar the reported rate in TRYPHAENA. Toxicity was manageable, with no patients experiencing symptomatic heart failure.
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- 2016
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183. The utility of repeated cytologic evaluation of cerebrospinal fluid in individuals with metastatic breast cancer.
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Patel JB, Xing J, Deeds D, Budd GT, Booth CN, and Abdul-Karim FW
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Introduction: Metastasis of breast cancer to the central nervous system, either in the brain parenchyma or leptomeninges (LMC), is a late feature of the disease . Detection of malignant cells in the cerebrospinal fluid (CSF) is the diagnostic standard for LMC. Repeated CSF examinations are often performed following an initial diagnosis positive for malignancy. This study evaluates the significance of repeated CSF evaluation in women with metastatic breast cancer to the central nervous system., Materials and Methods: Cases of adenocarcinoma of breast diagnosed by CSF cytology from 1990 through 2012 documenting: age, radiologic findings, treatment modality, and the number of repeated CSF cytology specimens and their respective interpretations., Results: Fifty-one patients were identified; 28 patients (54.9%) had a single initial positive CSF performed and 23 (45.1%) had multiple CSF cytology samples (range = 2-25, mean = 5.5). Despite interval "negative" and "atypical cells" results on CSF cytology specimens, all 23 patients with multiple samples had at least one follow-up positive CSF cytology sample., Conclusion: The prognosis of the patients with an initial CSF diagnosis of adenocarcinoma was poor, regardless of the respective interpretations on the repeated CSF specimens, even in the presence of interval negative CSF., (Copyright © 2016 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)
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- 2016
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184. Supplement use during an intergroup clinical trial for breast cancer (S0221).
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Zirpoli GR, Brennan PM, Hong CC, McCann SE, Ciupak G, Davis W, Unger JM, Budd GT, Hershman DL, Moore HC, Stewart J, Isaacs C, Hobday T, Salim M, Hortobagyi GN, Gralow JR, Albain KS, and Ambrosone CB
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Antioxidants administration & dosage, Female, Humans, Middle Aged, Odds Ratio, Risk Factors, Vitamins administration & dosage, Vitamins therapeutic use, Young Adult, Antioxidants therapeutic use, Breast Neoplasms drug therapy, Dietary Supplements
- Abstract
The use of supplements during chemotherapy is controversial, partly due to the potential effect of antioxidants on reduced efficacy of chemotherapy-related cytotoxicity. We examined supplement use among breast cancer patients registered to a clinical trial (SWOG 0221) before diagnosis and during treatment. Patients (n = 1,467) completed questionnaires regarding multivitamin and supplement use at trial registration (baseline) to capture use before diagnosis. Of these patients, 1,249 completed a 6-month followup questionnaire to capture use during treatment. We examined the use of vitamins C, D, E, B6, B12, folic acid, and calcium at these timepoints, as well as physician recommendations regarding supplement use. The use of vitamins C, E, folic acid, and calcium decreased during treatment, while the use of vitamin B6 increased. Five hundred seventy four patients (51 %) received no physician recommendations regarding supplement use. Among the remaining 49, 10 % were advised not to take multivitamins and/or supplements, 7 % were advised to use only multivitamins, and 32 % received recommendations to use multivitamins and/or supplements. Among patients who took vitamin C before diagnosis, those who were advised not to take supplements were >5 times more likely not to use of vitamin C during treatment than those not advised to stop use (OR = 5.27, 95 % CI 1.13-24.6). Previous non-users who were advised to take a multivitamin were nearly 5 times more likely to use multivitamins during treatment compared to those who received no recommendation (OR = 4.66, 95 % CI 2.10-10.3). In this clinical trial for high-risk breast cancer, supplement use generally decreased during treatment. Upon followup from the clinical trial, findings regarding supplement use and survival outcomes will better inform physician recommendations for patients on adjuvant chemotherapy.
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- 2013
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185. Delay to formalin fixation 'cold ischemia time': effect on ERBB2 detection by in-situ hybridization and immunohistochemistry.
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Portier BP, Wang Z, Downs-Kelly E, Rowe JJ, Patil D, Lanigan C, Budd GT, Hicks DG, Rimm DL, and Tubbs RR
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- Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Cytodiagnosis methods, Cytodiagnosis standards, Female, Fixatives, Formaldehyde, Humans, Immunohistochemistry, Reproducibility of Results, Time, Tissue Array Analysis, Tissue Fixation, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast metabolism, Cold Ischemia methods, In Situ Hybridization, Fluorescence methods, Receptor, ErbB-2 analysis
- Abstract
The American Society of Clinical Oncology/College of American Pathologists ERBB2 testing guidelines address several pre-analytical variables known to affect ERBB2 testing accuracy. According to 2010 updated guidelines, the pre-analytical variable of time to tissue fixation (cold ischemia time) should be kept to <1 h, however, little has been published about cold ischemia time and its significance in ERBB2 testing. To that end, this study evaluated ERBB2 status using two different FDA-approved in-situ hybridization methods and an FDA-approved immunohistochemistry (IHC) assay in the largest cohort to date (n=84) of invasive breast carcinomas with tracked cold ischemia time. Cold ischemia time was stratified into four groups (<1 h (n=45), 1-2 h (n=27), 2-3 h (n=6), and >3 h (n=6)) and ERBB2 status was evaluated in each group by IHC (4B5) and by in-situ hybridization methodologies (PathVysion(®) fluorescence in situ hybridization and the INFORM HER2(®) dual in situ DNA probe assay). Both in-situ hybridization methods were evaluated using three ERBB2 scoring criteria (dual-probe guidelines, single-probe guidelines, and the FDA package insert scoring instructions). Fluorescence in-situ hybridization (FISH) and INFORM HER2(®) demonstrated 100% concordance in the detection of ERBB2 amplification by all three scoring guidelines at all cold ischemia time points. Agreement between in-situ hybridization methodologies and IHC was superior using single-probe guidelines compared with dual probe or FDA scoring instructions. In addition, Inform HER2(®) in-situ hybridization signals were significantly more intense than FISH at all cold ischemia time points, however, no significant loss of either chromosome 17 or ERBB2 signal was detected by FISH or Inform HER2(®) in-situ hybridization in cold ischemia times up to 3 h. On the basis of our findings, cold ischemia time up to 3 h has no deleterious effect on the detection of ERBB2 via in-situ hybridization or IHC.
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- 2013
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186. Circulating tumor cells in biliary cancer: First step or false step?
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Budd GT
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- 2012
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187. Specific kinesin expression profiles associated with taxane resistance in basal-like breast cancer.
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Tan MH, De S, Bebek G, Orloff MS, Wesolowski R, Downs-Kelly E, Budd GT, Stark GR, and Eng C
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- Adenosine Triphosphate metabolism, Adult, Aged, Anthracyclines pharmacology, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Bridged-Ring Compounds therapeutic use, Cell Line, Tumor, Cluster Analysis, Docetaxel, Female, Gene Expression, Gene Expression Profiling, HEK293 Cells, Humans, Kinesins metabolism, Middle Aged, Neoplasm Staging, Paclitaxel pharmacology, Protein Binding, Taxoids therapeutic use, Vincristine pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms genetics, Bridged-Ring Compounds pharmacology, Drug Resistance, Neoplasm genetics, Kinesins genetics, Taxoids pharmacology
- Abstract
Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies. Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance. In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (P < 0.001) and paclitaxel (P < 0.001), but not to platinum-based chemotherapy, including carboplatin (P = 0.49) and cisplatin (P = 0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (P = 0.01); no KIF predicted resistance to fluorouracil-epirubicin-cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8-fold-change). Functional studies established that overexpression of KIFC3, KIF5A, and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. Mutation of the ATP-binding domain of a kinesin abolished its ability to mediate docetaxel resistance. Overall, kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissues. Our results suggest a novel approach for drug development to overcome taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors.
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- 2012
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188. S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.
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Blanke CD, Chansky K, Christman KL, Hundahl SA, Issell BF, Van Veldhuizen PJ Jr, Budd GT, Abbruzzese JL, and Macdonald JS
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- Adenocarcinoma secondary, Adult, Aged, Aged, 80 and over, Female, Fluorouracil administration & dosage, Humans, Leucovorin administration & dosage, Male, Middle Aged, Neoplasm Staging, Stomach Neoplasms pathology, Survival Rate, Treatment Outcome, Trimetrexate administration & dosage, Young Adult, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Stomach Neoplasms drug therapy
- Abstract
Objective: The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting., Methods: Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression., Results: Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia., Conclusions: This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.
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- 2010
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189. Phase II clinical trial of imatinib mesylate in therapy of KIT and/or PDGFRalpha-expressing Ewing sarcoma family of tumors and desmoplastic small round cell tumors.
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Chao J, Budd GT, Chu P, Frankel P, Garcia D, Junqueira M, Loera S, Somlo G, Sato J, and Chow WA
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- Abdominal Neoplasms metabolism, Abdominal Neoplasms pathology, Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Benzamides, Bone Neoplasms metabolism, Bone Neoplasms pathology, Carcinoma, Small Cell metabolism, Carcinoma, Small Cell pathology, Female, Humans, Imatinib Mesylate, Male, Middle Aged, Neuroectodermal Tumors, Primitive drug therapy, Neuroectodermal Tumors, Primitive metabolism, Neuroectodermal Tumors, Primitive pathology, Sarcoma, Ewing metabolism, Sarcoma, Ewing pathology, Survival Rate, Treatment Outcome, Abdominal Neoplasms drug therapy, Bone Neoplasms drug therapy, Carcinoma, Small Cell drug therapy, Piperazines therapeutic use, Proto-Oncogene Proteins c-kit metabolism, Pyrimidines therapeutic use, Receptor, Platelet-Derived Growth Factor beta metabolism, Sarcoma, Ewing drug therapy
- Abstract
Background: We have previously shown that the receptor tyrosine kinases, KIT and PDGFRalpha, are expressed on ESFT cell lines, and that imatinib induces dose-dependent apoptosis (1). We conducted a Phase II trial to evaluate the effectiveness of imatinib for patients with recurrent ESFT or DSRCT expressing KIT and/or PDGFRalpha., Patients and Methods: Patients were selected for tumor immunohisto-chemical expression > or =2+/4+ for KIT or PDGFRalpha. Imatinib was administered orally 400 mg twice/day for 28 days/course. Primary endpoint was response., Results: Seven patients were enrolled and evaluated. One patient with 3+/4+ PDGFRalpha and 3+/4+ KIT expression had a partial response through 8 courses. 4 patients had progression after 1 cycle. Two patients were not evaluable due to one early death and one refusing treatment., Conclusion: This study intended to enrich for molecular factors that potentially predict response. Given the poor prognosis with recurrent ESFT, further studies with other novel KIT and PDGFRalpha inhibitors are needed.
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- 2010
190. The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy.
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Zhang Y, Sieuwerts AM, McGreevy M, Casey G, Cufer T, Paradiso A, Harbeck N, Span PN, Hicks DG, Crowe J, Tubbs RR, Budd GT, Lyons J, Sweep FC, Schmitt M, Schittulli F, Golouh R, Talantov D, Wang Y, and Foekens JA
- Subjects
- Adult, Aged, Chemotherapy, Adjuvant, Female, Gene Expression, Humans, Kaplan-Meier Estimate, Middle Aged, Neoplasm Staging, Prognosis, Risk Factors, Selective Estrogen Receptor Modulators therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Tamoxifen therapeutic use
- Abstract
Purpose: To assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature., Methods: In 300 lymph node-negative (LNN), estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion., Results: In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis [hazard ratio (HR), 4.62; P = 0.0248]. These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52; P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen., Conclusions: The 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of loco-regional relapse and a reduction in risk for contralateral breast cancer might justify hormonal therapy in these patients.
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- 2009
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191. Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial.
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Olson JA Jr, Budd GT, Carey LA, Harris LA, Esserman LJ, Fleming GF, Marcom PK, Leight GS Jr, Giuntoli T, Commean P, Bae K, Luo J, and Ellis MJ
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- Aged, Aged, 80 and over, Breast Neoplasms pathology, Breast Neoplasms surgery, Carcinoma, Ductal, Breast pathology, Carcinoma, Ductal, Breast surgery, Carcinoma, Lobular pathology, Carcinoma, Lobular surgery, Chemotherapy, Adjuvant, Female, Humans, Letrozole, Mastectomy, Segmental, Middle Aged, Multivariate Analysis, Neoplasm Staging, Treatment Outcome, Aromatase Inhibitors administration & dosage, Breast Neoplasms drug therapy, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Lobular drug therapy, Neoadjuvant Therapy, Nitriles administration & dosage, Triazoles administration & dosage
- Abstract
Background: Neoadjuvant aromatase inhibitor therapy has been reported to improve surgical outcomes for postmenopausal women with clinical stage II or III hormone receptor-positive breast cancer. A multicenter phase II clinical trial was conducted to investigate the value of this approach for US surgical practice., Study Design: One hundred fifteen postmenopausal women with >2 cm, estrogen receptor (ER) or progesterone receptor (PgR)-positive breast cancer were enrolled in a trial of 16 to 24 weeks of letrozole 2.5 mg daily before operation., Results: One hundred six patients were eligible for primary analysis, 96 underwent operations, 7 received chemotherapy after progressive disease, and 3 did not undergo an operation. Baseline surgical status was marginal for breast-conserving surgery (BCS) in 48 (45%), 47 were definitely ineligible for BCS (44%), and 11 were inoperable by standard mastectomy (10%). Overall Response Evaluation Criteria In Solid Tumors clinical response rate in the breast was 62%, with 12% experiencing progressive disease. Fifty percent underwent BCS, including 30 of 46 (65%) patients who were initially marginal for BCS and 15 of 39 (38%) patients who were initially ineligible for BCS. All 11 inoperable patients successfully underwent operations, including 3 (27%) who had BCS. Nineteen percent of patients undergoing mastectomy had a pathologic T1 tumor, suggesting that some highly responsive tumors were overtreated surgically., Conclusions: Neoadjuvant aromatase inhibitor improves operability and facilitates BCS, but there was considerable variability in responsiveness. Better techniques to predict response, determine residual tumor burden before operation, and greater willingness to attempt BCS in responsive patients could additionally improve the rate of successful BCS.
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- 2009
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192. Incorporating the Oncotype DX breast cancer assay into community practice: an expert Q&A and case study sampling.
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Mamounas EP, Budd GT, and Miller KD
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- Antineoplastic Agents, Hormonal therapeutic use, Chemotherapy, Adjuvant, Humans, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms therapy, Gene Expression Profiling
- Abstract
Advances in breast cancer research have confirmed that this malignancy is not a single disease, but rather a collection of genetically distinct diseases with different treatment requirements. In recent years, several studies have confirmed the clinical validity of the Oncotype DX breast cancer assay, not only as a way to predict recurrence but also as a tool for determining therapeutic benefit from adjuvant chemotherapy. Recently, Drs. Terry Mamounas, G. Thomas Budd, and Kathy Miller answered questions about the Oncotype DX assay that are particularly relevant to routine clinical practice. This expert dialog provides a useful update and essential clinical insights about how, why, and when community oncologists may want to incorporate this multi-gene assay into their care of breast cancer patients. In addition, sample case studies offer tangible examples of the practical application of Oncotype DX.
- Published
- 2008
193. Incorporating the Oncotype DX breast cancer assay into community practice: An expert Q & A and case study sampling.
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Mamounas E, Budd GT, and Miller K
- Subjects
- Adult, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms classification, Breast Neoplasms surgery, Chemotherapy, Adjuvant methods, Clinical Trials as Topic, Female, Genotype, Humans, Middle Aged, Polymerase Chain Reaction methods, Receptors, Estrogen analysis, Tamoxifen therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Gene Expression Profiling methods
- Published
- 2008
194. Incidence of advanced symptomatic disease as primary endpoint in screening and prevention trials.
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Obuchowski NA, Schoenhagen P, Modic MT, Meziane M, and Budd GT
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- Humans, Incidence, Mass Screening methods, Risk Factors, Survival Analysis, Survival Rate, Chronic Disease mortality, Epidemiologic Measurements, Mass Screening statistics & numerical data, Proportional Hazards Models, Randomized Controlled Trials as Topic methods, Risk Assessment methods
- Abstract
Objective: Randomized clinical trials (RCTs) using disease-specific mortality as the primary outcome are the gold standard for evaluating the efficacy of screening tests. These trials require thousands of subjects and 8-10 years of follow-up; often the imaging technology has changed by the end of the trial., Conclusion: We propose the incidence of symptomatic disease as an alternative to disease-specific mortality. This endpoint is sensitive to the benefit of screening, correlates with patients' quality of life and societal costs, and can dramatically reduce the sample size and follow-up requirements of RCTs.
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- 2007
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195. Phase 1 trial of Anvirzel in patients with refractory solid tumors.
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Mekhail T, Kaur H, Ganapathi R, Budd GT, Elson P, and Bukowski RM
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- Adolescent, Adult, Aged, Antineoplastic Agents therapeutic use, Cardenolides therapeutic use, Electrocardiography, Female, Humans, Male, Middle Aged, Antineoplastic Agents adverse effects, Cardenolides adverse effects, Maximum Tolerated Dose, Neoplasms drug therapy
- Abstract
Anvirzel is an aqueous extract of the plant Nerium oleander which has been utilized to treat patients with advanced malignancies. The current study reports a phase 1 trial to determine the maximum tolerated dose (MTD) and safety of Anvirzel in patients with advanced, refractory solid tumors. Patients were randomized to receive this agent by intramuscular injection at doses of 0.1, 0.2, 0.4 ml/m2/day with subsequent patients receiving 0.8 or 1.2 ml/m2/day sequentially. Eighteen patients were enrolled and completed at least one treatment cycle of three weeks. Most patients developed mild injection site pain (78%). Other toxicities included fatigue, nausea, and dyspnea. Traditional dose limiting toxicity was not seen, but the MTD was defined by injection volume as 0.8 ml/m2/day. No objective anti-tumor responses were seen. Anvirzel can be safely administered at doses up to 1.2 ml/m2/day, with the amount administered intramuscularly limited by volume. The recommended phase II dose level is 0.8 ml/m2/day.
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- 2006
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196. HER2 status in bilateral breast cancer.
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Crowe JP, Patrick RJ, Rybicki LA, Budd GT, Escobar PF, Tubbs RR, and Hicks DG
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- Biomarkers, Tumor metabolism, Female, Humans, Medical Records statistics & numerical data, Neoplasm Invasiveness, United States epidemiology, Women's Health, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genes, erbB-2, Receptor, ErbB-2 metabolism
- Abstract
Background: The purpose of this study was to identify correlates of HER2 status for patients with bilateral breast cancer., Methods: Data were collected prospectively in our institutional review board approved patient registry for all patients with asynchronous (ABBC) and synchronous (SBBC) bilateral infiltrating breast cancer whose HER2 assays were performed at our laboratory using FISH. Data were analyzed using the Wilcoxon rank sum and Chi-square test., Results: Data were available for 98 tumors in 49 patients. Patients diagnosed with SBBC were more likely to be white (P = 0.023); to have bilateral HER2 non-amplified tumors (P = 0.022) and to be older at diagnosis (P = 0.025) compared to those with ABBC. Patients with one HER2 amplified tumor were likely to have at least one tumor be hormone receptor negative and to have ABBC., Conclusions: Only 16% of patients in this study had one tumor that was HER2 amplified; no patient had bilateral HER2 amplified tumors.
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- 2006
197. Phase I trial of vinorelbine and diphenylhydantoin in patients with refractory carcinoma.
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Hutson TE, Ganapathi R, Elson P, Mekhail T, Olencki T, Budd GT, and Bukowski RM
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic adverse effects, Cell Line, Tumor, Cohort Studies, Dose-Response Relationship, Drug, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Drug Synergism, Drug Therapy, Combination, Female, Humans, Injections, Intravenous, Male, Maximum Tolerated Dose, Middle Aged, Vinblastine administration & dosage, Vinblastine adverse effects, Vinorelbine, Anticonvulsants pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Neoplasms drug therapy, Phenytoin pharmacology, Vinblastine analogs & derivatives, Vinblastine pharmacology
- Abstract
Unlabelled: The anti-epileptic diphenylhydantoin (DPH; Dilantin) selectively enhances the in vitro cytotoxicity of vinca microtubule poisons in both parent sensitive and multi-drug resistant (MDR) human tumor cells. The in vivo clinical activity of this combination has not been fully evaluated., Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and preliminary antitumor activity of the combination of intravenous (IV) bolus vinorelbine (VRL) and oral diphenylhydantoin (DPH) in patients (pts) with refractory solid tumors., Methods: Cohorts of 3-6 pts with refractory cancer were treated with escalating doses of weekly IV bolus VRL (I -20.0 mg/m(2); II -22.5 mg/m(2); III -25.0 mg/m(2); IV -27.5 mg/m(2); V -30.0 mg/m(2); VI -32.5 mg/m(2)) combined with a fixed oral dose of DPH (400 mg/day) until MTD or progression. During each 35 day cycle, pts received DPH 400 mg/day administered orally on Days -6 to Day +22 and weekly IV bolus infusion of VRL on Days +1, +8, +15, and +22. The cohort treated at the MTD was expanded to further define toxicity., Results: A total of 25 evaluable pts. (9 men; 16 women) were treated with VRL and DPH at dose levels I ( n = 5), II ( n = 3), III ( n = 2), IV ( n = 3), V ( n = 7) and VI ( n = 5) in 5 week cycles over a 16 month period. Dose limiting toxicity occurred at dose level VI (VRL 32.5 mg/m(2)) and included grade 3 leukopenia ( n = 2), grade 3 neutropenia ( n = 1) and grade 4 neutropenia ( n = 1) occurring within the first cycle of treatment. There were no responses, however 9 pts had stable disease of variable duration (8-56 weeks) and received a median of 2 cycles of treatment (range 2-14)., Conclusion: Intravenous bolus administration of VRL and oral administration of a fixed dose of DPH was well tolerated according to the schedule reported here. Although there were no responses, several patients had prolonged disease stabilization. The recommended phase II dose of VRL when used in this combination is 30 mg/m(2).
- Published
- 2004
- Full Text
- View/download PDF
198. Metronomic therapy for breast cancer.
- Author
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Kaur H and Budd GT
- Subjects
- Clinical Trials as Topic, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Maximum Tolerated Dose, Neovascularization, Pathologic drug therapy, Women's Health, Antineoplastic Agents administration & dosage, Breast Neoplasms drug therapy
- Abstract
Conventional cytotoxic chemotherapeutic drugs treat cancer either by direct killing or by inhibition of growth of cycling tumor cells. In addition, evidence suggests that cytotoxic agents may inhibit tumor growth through an antiangiogenic mechanism. "Metronomic" or frequent continuous administration of the same chemotherapeutic agents at lower doses may optimize their antiangiogenic properties. The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs. Preclinical studies have shown that integrating chemotherapy with antiangiogenic drugs can improve efficacy and circumvent the toxicity and drug resistance associated with standard or high-dose chemotherapy. Preliminary clinical studies have shown similar results. Further confirmation of this concept is required with randomized, controlled clinical trials.
- Published
- 2004
- Full Text
- View/download PDF
199. Management of angiosarcoma.
- Author
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Budd GT
- Subjects
- Age Factors, Angiogenesis Inhibitors therapeutic use, Female, Head and Neck Neoplasms etiology, Head and Neck Neoplasms pathology, Hemangiosarcoma etiology, Hemangiosarcoma pathology, Humans, Interferons therapeutic use, Liver Neoplasms etiology, Liver Neoplasms therapy, Lymphedema pathology, Male, Neoplasm Recurrence, Local, Prognosis, Sex Factors, Skin Neoplasms therapy, Treatment Outcome, Head and Neck Neoplasms therapy, Hemangiosarcoma therapy
- Abstract
Angiosarcoma is an uncommon tumor that presents in several scenarios. Although angiosarcoma can occur in any organ, it typically presents in the following settings: 1) in the face or scalp among elderly patients, 2) with chronic lymphedema, 3) after radiotherapy, or 4) as a hepatic primary. In all of these situations, angiosarcoma is associated with multifocality and an insidious growth pattern, making local control difficult. Doxorubicin-ifosfamide chemotherapy produces a modest response rate, and paclitaxel appears to be useful for scalp and facial angiosarcomas. However, improvement in systemic therapy is clearly needed. One logical strategy is to investigate antiangiogenic therapies in this endothelial tumor. Improved therapy for this tumor will come only with greater understanding of its biology.
- Published
- 2002
- Full Text
- View/download PDF
200. Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer.
- Author
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Leichman CG, Chansky K, Macdonald JS, Doukas MA, Budd GT, Giguere JK, and Abbruzzese JL
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Protocols, Colorectal Neoplasms enzymology, Confidence Intervals, Dihydrouracil Dehydrogenase (NADP), Enzyme Inhibitors adverse effects, Enzyme Inhibitors therapeutic use, Female, Fluorouracil adverse effects, Fluorouracil chemistry, Humans, Male, Middle Aged, Oxidoreductases metabolism, Southwestern United States, Survival Rate, Treatment Failure, Uracil adverse effects, Colorectal Neoplasms drug therapy, Fluorouracil therapeutic use, Oxidoreductases antagonists & inhibitors, Uracil analogs & derivatives, Uracil therapeutic use
- Abstract
Purpose: To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response., Patients and Methods: Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses., Results: Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%., Conclusions: This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.
- Published
- 2002
- Full Text
- View/download PDF
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