30 results on '"Prowell, TM"'
Search Results
2. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer
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Blumenthal, GM, Bunn, PA, Chaft, JE, McCoach, CE, Perez, EA, Scagliotti, GV, Carbone, DP, Aerts, HJWL, Aisner, DL, Bergh, J, Berry, DA, Jarkowski, A, Botwood, N, Cross, DAE, Diehn, M, Drezner, NL, Doebele, RC, Blakely, CM, Eberhardt, WEE, Felip, E, Gianni, L, Keller, SP, Leavey, PJ, Malik, S, Pignatti, F, Prowell, TM, Redman, MW, Rizvi, NA, Rosell, R, Rusch, V, de Ruysscher, D, Schwartz, LH, Sridhara, R, Stahel, RA, Swisher, S, Taube, JM, Travis, WD, Keegan, P, Wiens, JR, Wistuba, II, Wynes, MW, Hirsch, FR, and Kris, MG
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Pathologic response ,Neoadjuvant therapy ,Induction chemotherapy ,Resectable lung cancer ,Preoperative therapy - Abstract
This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.
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- 2018
3. Abstract P5-17-01: A definition of a high-risk early-breast cancer population based on data from the collaborative trials in neoadjuvant breast cancer (CTNeoBC) meta-analysis
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Cortazar, P, primary, Zhang, L, additional, Untch, M, additional, Mehta, K, additional, Constantino, J, additional, Wolmark, N, additional, Bonnefoi, H, additional, Piccart, M, additional, Gianni, L, additional, Valagussa, P, additional, Zujewski, JA, additional, Justice, R, additional, Loibl, S, additional, Swain, SM, additional, Bogaerts, J, additional, Baselga, J, additional, Prowell, TM, additional, Rastogi, P, additional, Sridhara, R, additional, Tang, S, additional, Pazdur, R, additional, Mamounas, E, additional, and von Minckwitz, G, additional
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- 2013
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4. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma.
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Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Sridhara R, and Pazdur R
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This report summarizes the U.S. Food and Drug Administration (FDA)'s approval of temsirolimus (Torisel(R)), on May 30, 2007, for the treatment of advanced renal cell carcinoma (RCC). Information provided includes regulatory history, study design, study results, and literature review. A multicenter, three-arm, randomized, open-label study was conducted in previously untreated patients with poor-prognosis, advanced RCC. The study objectives were to compare overall survival (OS), progression-free survival (PFS), objective response rate, and safety in patients receiving interferon (IFN)-alpha versus those receiving temsirolimus alone or in combination with IFN-alpha. In the second planned interim analysis of the intent-to-treat population (n = 626), there was a statistically significant longer OS time in the temsirolimus (25 mg) arm than in the IFN-alpha arm (median, 10.9 months versus 7.3 months; hazard ratio [HR], 0.73; p = .0078). The combination of temsirolimus (15 mg) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone. There was also a statistically significant longer PFS time for the temsirolimus (25 mg) arm than for the IFN-alpha arm (median, 5.5 months versus 3.1 months; HR, 0.66, p = .0001). Common adverse reactions reported in patients receiving temsirolimus were rash, asthenia, and mucositis. Common laboratory abnormalities were anemia, hyperglycemia, hyperlipidemia, and hypertriglyceridemia. Serious but rare cases of interstitial lung disease, bowel perforation, and acute renal failure were observed. Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC. [ABSTRACT FROM AUTHOR]
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- 2010
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5. Extended adjuvant therapy for breast cancer--how much is enough?
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Prowell TM and Stearns V
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- 2007
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6. Disease-free survival was greater with letrozole than tamoxifen in postmenopausal women with early breast cancer.
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Prowell TM and Stearns V
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- 2006
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7. Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.
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Litton JK, Regan MM, Pusztai L, Rugo HS, Tolaney SM, Garrett-Mayer E, Amiri-Kordestani L, Basho RK, Best AF, Boileau JF, Denkert C, Foster JC, Harbeck N, Jacene HA, King TA, Mason G, O'Sullivan CC, Prowell TM, Richardson AL, Sepulveda KA, Smith ML, Tjoe JA, Turashvili G, Woodward WA, Butler LP, Schwartz EI, and Korde LA
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- Humans, Female, Neoadjuvant Therapy methods, Research Design, Progression-Free Survival, Breast Neoplasms drug therapy, Breast Neoplasms surgery
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Purpose: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points., Methods: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated., Results: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial., Conclusion: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.
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- 2023
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8. Postmarketing Colitis Cases Associated With Alpelisib Use Reported to the US Food and Drug Administration.
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Sullivan KM, Dores GM, Nayernama A, Prowell TM, Pradhan SM, Osgood C, and Jones SC
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- Humans, United States epidemiology, United States Food and Drug Administration, Antineoplastic Combined Chemotherapy Protocols, Thiazoles, Colitis chemically induced
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- 2022
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9. The (R)evolution of Social Media in Oncology: Engage, Enlighten, and Encourage.
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Morgan G, Agarwal N, Choueiri TK, Dizon DS, Hamilton EP, Markham MJ, Lewis M, Prowell TM, Rugo HS, Subbiah V, and West HL
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- Humans, Medical Oncology, Social Media
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Summary: Social media (SoMe) platforms have the ability to strengthen the oncology community, leading to intellectual connections that with time develop into friendships. SoMe has immense potential in all areas of medicine, and SoMe in oncology is proof of this, raising awareness about clinical trials, promoting cancer prevention techniques, amplifying oncology information, enabling diverse viewpoints into conversations, as well as educating colleagues regardless of geography., (©2022 American Association for Cancer Research.)
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- 2022
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10. U.S. FDA Drug Approvals for Gynecological Malignancies: A Decade in Review.
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Arora S, Narayan P, Ison G, Berman T, Suzman DL, Wedam S, Prowell TM, Ghosh S, Philip R, Osgood CL, Gao JJ, Shah M, Krol D, Wahby S, Royce M, Brus C, Bloomquist EW, Fiero MH, Tang S, Pazdur R, Ibrahim A, Amiri-Kordestani L, and Beaver JA
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- Drug Approval, Female, Humans, United States, United States Food and Drug Administration, Antineoplastic Agents therapeutic use, Genital Neoplasms, Female drug therapy
- Abstract
Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed., (©2021 American Association for Cancer Research.)
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- 2022
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11. U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review.
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Arora S, Narayan P, Osgood CL, Wedam S, Prowell TM, Gao JJ, Shah M, Krol D, Wahby S, Royce M, Ghosh S, Philip R, Ison G, Berman T, Brus C, Bloomquist EW, Fiero MH, Tang S, Pazdur R, Ibrahim A, Amiri-Kordestani L, and Beaver JA
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- Drug Approval, Female, Humans, Medical Oncology, United States, United States Food and Drug Administration, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy
- Abstract
Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described., (©2021 American Association for Cancer Research.)
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- 2022
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12. Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.
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Gao JJ, Cheng J, Prowell TM, Bloomquist E, Tang S, Wedam SB, Royce M, Krol D, Osgood C, Ison G, Sridhara R, Pazdur R, Beaver JA, and Amiri-Kordestani L
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- Adult, Aged, Breast Neoplasms metabolism, Breast Neoplasms pathology, Clinical Trials, Phase III as Topic, Estrogen Receptor Antagonists therapeutic use, Female, Humans, Middle Aged, Neoplasm Metastasis, Receptor, ErbB-2 metabolism, Receptors, Progesterone metabolism, Survival Rate, United States, United States Food and Drug Administration, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms mortality, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Fulvestrant therapeutic use
- Abstract
Background: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant., Methods: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating., Findings: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs., Interpretation: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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13. Model Development of CDK4/6 Predicted Efficacy in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer.
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Mason J, Gong Y, Amiri-Kordestani L, Wedam S, Gao JJ, Prowell TM, Singh H, Amatya A, Tang S, Pazdur R, Kuhn P, Blumenthal GM, and Beaver JA
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- Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Female, Hormones, Humans, Receptor, ErbB-2, Breast Neoplasms drug therapy
- Abstract
Purpose: Three cyclin-dependent kinase 4/6 inhibitors (CDKIs) are approved by the US Food and Drug Administration for the treatment of patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with hormonal therapy (HT). We hypothesized that on an individual basis, efficacy outcomes and adverse event (AE) development can be predicted using baseline patient and tumor characteristics., Methods: Individual-level data from seven randomized controlled trials submitted to the US Food and Drug Administration for new or supplemental marketing applications of CDKIs were pooled. Progression-free survival (PFS), overall survival (OS), and AE prediction models were developed for specific treatment regimens (HT v HT plus CDKI). An individual's characteristics were used in all models simultaneously to create a group of predicted outcomes that are comparable across treatment settings., Results: Accuracy of the PFS and OS prediction models for HT were 66% and 64%, respectively, with the strongest predictors being menopausal status and therapy line. The corresponding AE prediction models resulted in an average area under the curve of 0.613. Accuracy of the PFS and OS prediction models for HT plus CDKI were 62% and 63%, respectively, with the strongest predictors being histologic grade for both. The corresponding AE prediction models resulted in an average area under the curve of 0.639., Conclusion: This exploratory analysis demonstrated that models of efficacy outcomes and AE development can be developed using baseline patient and tumor characteristics. Comparison of paired models can inform treatment selection for individuals on the basis of the patient's personalized goals and concerns. Although use of CDKIs is standard of care in the first- or second-line setting, this model provides prognostic information that may inform individual treatment decisions., Competing Interests: Yutao GongEmployment: BeiGeneStock and Other Ownership Interests: BeiGene Jennifer J. GaoEmployment: WorldCare Clinical LLC (part time) Gideon M. BlumenthalEmployment: MerckStock and Other Ownership Interests: MerckNo other potential conflicts of interest were reported.
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- 2021
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14. FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.
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Narayan P, Prowell TM, Gao JJ, Fernandes LL, Li E, Jiang X, Qiu J, Fan J, Song P, Yu J, Zhang X, King-Kallimanis BL, Chen W, Ricks TK, Gong Y, Wang X, Windsor K, Rhieu SY, Geiser G, Banerjee A, Chen X, Reyes Turcu F, Chatterjee DK, Pathak A, Seidman J, Ghosh S, Philip R, Goldberg KB, Kluetz PG, Tang S, Amiri-Kordestani L, Theoret MR, Pazdur R, and Beaver JA
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms genetics, Breast Neoplasms mortality, Breast Neoplasms pathology, Double-Blind Method, Drug Approval, Female, Fulvestrant adverse effects, Fulvestrant pharmacology, Humans, Male, Middle Aged, Neoplasm Metastasis, Patient Reported Outcome Measures, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Thiazoles adverse effects, Thiazoles pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Class I Phosphatidylinositol 3-Kinases genetics, Fulvestrant administration & dosage, Mutation, Thiazoles administration & dosage
- Abstract
On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia., (©2020 American Association for Cancer Research.)
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- 2021
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15. Words Matter: Use of Respectful Language in Oncology.
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Zitella LJ and Prowell TM
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During JADPRO Live Virtual 2020, Conference Chair Laura J. Zitella, MS, RN, ACNP-BC, AOCN®, spoke with Tatiana M. Prowell, MD, about overcoming implicit bias, the power of language, and creating a culture of respect in oncology for both patients and health-care professionals., Competing Interests: Dr. Prowell and Ms. Zitella had no conflicts of interest to disclose., (© 2021 Harborside™.)
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- 2021
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16. Ethnicity-based differences in breast cancer features and responsiveness to CDK4/6 inhibitors combined with endocrine therapy - Authors' reply.
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Gao JJ, Cheng J, Beaver JA, and Prowell TM
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- Cyclin-Dependent Kinase 4, Humans, United States, United States Food and Drug Administration, Cyclin-Dependent Kinase 6, Ethnicity
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- 2020
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17. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis.
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Gao JJ, Cheng J, Bloomquist E, Sanchez J, Wedam SB, Singh H, Amiri-Kordestani L, Ibrahim A, Sridhara R, Goldberg KB, Theoret MR, Kluetz PG, Blumenthal GM, Pazdur R, Beaver JA, and Prowell TM
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Aromatase Inhibitors adverse effects, Breast Neoplasms chemistry, Breast Neoplasms mortality, Breast Neoplasms pathology, Clinical Trials, Phase III as Topic, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase 6 metabolism, Drug Approval, Female, Humans, Middle Aged, Neoplasm Metastasis, Progression-Free Survival, Protein Kinase Inhibitors adverse effects, Randomized Controlled Trials as Topic, Risk Factors, Signal Transduction, Time Factors, United States, United States Food and Drug Administration, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Aromatase Inhibitors administration & dosage, Biomarkers, Tumor analysis, Breast Neoplasms drug therapy, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Protein Kinase Inhibitors administration & dosage, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Receptors, Progesterone analysis
- Abstract
Background: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity., Methods: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models., Findings: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64)., Interpretation: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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18. Outcomes of Older Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis.
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Howie LJ, Singh H, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S, Sridhara R, Sanchez J, Prowell TM, Kluetz PG, King-Kallimanis BL, Gao JJ, Ibrahim A, Goldberg KB, Theoret M, Pazdur R, and Beaver JA
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- Aged, Aged, 80 and over, Aromatase Inhibitors therapeutic use, Breast Neoplasms mortality, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Female, Humans, Middle Aged, Progression-Free Survival, Protein Kinase Inhibitors therapeutic use, Randomized Controlled Trials as Topic, Receptors, Estrogen biosynthesis, Receptors, Progesterone biosynthesis, Treatment Outcome, United States, United States Food and Drug Administration, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy
- Abstract
Purpose: Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women., Patients and Methods: We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model., Results: For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor., Conclusion: There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.
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- 2019
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19. Residual Disease after Neoadjuvant Therapy - Developing Drugs for High-Risk Early Breast Cancer.
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Prowell TM, Beaver JA, and Pazdur R
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- Breast Neoplasms pathology, Breast Neoplasms therapy, Female, Humans, Neoadjuvant Therapy, Neoplasm Staging, Neoplasm, Residual, Receptor, ErbB-2 analysis, Risk Factors, Survival Analysis, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy
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- 2019
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20. Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology.
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Hobbs BP, Barata PC, Kanjanapan Y, Paller CJ, Perlmutter J, Pond GR, Prowell TM, Rubin EH, Seymour LK, Wages NA, Yap TA, Feltquate D, Garrett-Mayer E, Grossman W, Hong DS, Ivy SP, Siu LL, Reeves SA, and Rosner GL
- Subjects
- Humans, Medical Oncology, Societies, Medical, Drug Approval, Drug Development, Drugs, Investigational therapeutic use, Neoplasms drug therapy, Research Design
- Abstract
Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval., (© The Author(s) 2018. Published by Oxford University Press.)
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- 2019
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21. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.
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Blumenthal GM, Bunn PA Jr, Chaft JE, McCoach CE, Perez EA, Scagliotti GV, Carbone DP, Aerts HJWL, Aisner DL, Bergh J, Berry DA, Jarkowski A, Botwood N, Cross DAE, Diehn M, Drezner NL, Doebele RC, Blakely CM, Eberhardt WEE, Felip E, Gianni L, Keller SP, Leavey PJ, Malik S, Pignatti F, Prowell TM, Redman MW, Rizvi NA, Rosell R, Rusch V, de Ruysscher D, Schwartz LH, Sridhara R, Stahel RA, Swisher S, Taube JM, Travis WD, Keegan P, Wiens JR, Wistuba II, Wynes MW, Hirsch FR, and Kris MG
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- Humans, Prognosis, Antineoplastic Agents therapeutic use, Lung Neoplasms drug therapy, Neoadjuvant Therapy
- Abstract
This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence., (Published by Elsevier Inc.)
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- 2018
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22. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement.
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Kim ES, Bruinooge SS, Roberts S, Ison G, Lin NU, Gore L, Uldrick TS, Lichtman SM, Roach N, Beaver JA, Sridhara R, Hesketh PJ, Denicoff AM, Garrett-Mayer E, Rubin E, Multani P, Prowell TM, Schenkel C, Kozak M, Allen J, Sigal E, and Schilsky RL
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- Eligibility Determination, Humans, Medical Oncology, United States, Biomedical Research methods, Clinical Trials as Topic, Early Detection of Cancer methods
- Abstract
Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention's benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.
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- 2017
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23. Seamless Oncology-Drug Development.
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Prowell TM, Theoret MR, and Pazdur R
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- Drug Discovery, Humans, Therapeutic Human Experimentation, United States, United States Food and Drug Administration, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Clinical Trials as Topic standards, Drug Approval organization & administration, Neoplasms drug therapy
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- 2016
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24. Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials.
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Theoret MR, Pai-Scherf LH, Chuk MK, Prowell TM, Balasubramaniam S, Kim T, Kim G, Kluetz PG, Keegan P, and Pazdur R
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- Clinical Trials as Topic methods, Humans, Medical Oncology methods, United States, United States Food and Drug Administration, Antineoplastic Agents therapeutic use, Drugs, Investigational therapeutic use, Neoplasms drug therapy
- Abstract
In 1962, the passage of the Kefauver-Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes "adequate and well-controlled" clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this "phased" approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions., (©2015 American Association for Cancer Research.)
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- 2015
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25. Pathological complete response and accelerated drug approval in early breast cancer.
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Prowell TM and Pazdur R
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- Female, Humans, Time Factors, United States, United States Food and Drug Administration, Breast Neoplasms drug therapy, Chemotherapy, Adjuvant, Drug Approval
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- 2012
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26. A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.
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Higgins MJ, Prowell TM, Blackford AL, Byrne C, Khouri NF, Slater SA, Jeter SC, Armstrong DK, Davidson NE, Emens LA, Fetting JH, Powers PP, Wolff AC, Green H, Thibert JN, Rae JM, Folkerd E, Dowsett M, Blumenthal RS, Garber JE, and Stearns V
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Breast Neoplasms genetics, C-Reactive Protein metabolism, Estrogens blood, Female, Humans, Hydroxymethylglutaryl CoA Reductases genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Lipids blood, Middle Aged, Quality of Life, Simvastatin adverse effects, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Breast Neoplasms prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Simvastatin administration & dosage
- Abstract
Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.
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- 2012
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27. Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole.
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Prowell TM, Blackford AL, Byrne C, Khouri NF, Dowsett M, Folkerd E, Tarpinian KS, Powers PP, Wright LA, Donehower MG, Jeter SC, Armstrong DK, Emens LA, Fetting JH, Wolff AC, Garrett-Mayer E, Skaar TC, Davidson NE, and Stearns V
- Subjects
- Aged, Anastrozole, Aromatase Inhibitors therapeutic use, Breast metabolism, Breast Neoplasms blood, Breast Neoplasms drug therapy, Carcinoma, Ductal, Breast blood, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Lobular blood, Carcinoma, Lobular drug therapy, Chemotherapy, Adjuvant, Female, Humans, Mammography, Middle Aged, Postmenopause, Prognosis, Prospective Studies, Breast pathology, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular pathology, Estrogens blood, Nitriles therapeutic use, Triazoles therapeutic use
- Abstract
Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes., (2011 AACR)
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- 2011
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28. Selecting endocrine therapy for breast cancer: what role does HER-2/neu status play?
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Prowell TM and Armstrong DK
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- Clinical Trials as Topic, Drug Resistance, Neoplasm, Female, Humans, Prognosis, Treatment Outcome, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor analysis, Breast Neoplasms drug therapy, Neoplasms, Hormone-Dependent drug therapy, Receptor, ErbB-2 metabolism
- Abstract
Most women with breast cancer that overexpresses either estrogen (ER+) or progesterone receptors (PR+) will be treated with an endocrine agent. Although ER and PR are the only validated predictive markers of response to hormonal therapy, many women with hormone receptor-positive (HR+) tumors will fail to respond to endocrine treatment or develop hormone resistant disease. Another tumor marker, HER-2/neu, is an oncogene whose amplification or protein overexpression predicts response to a monoclonal antibody targeting HER-2/neu, as well as to anthracycline-based chemotherapy. Preclinical and some clinical data suggest that HER-2/neu positivity may also predict for relative resistance to endocrine therapy. Interpretation of clinical data addressing this issue is confounded by largely retrospective study designs and considerable heterogeneity in patient populations and methods of marker detection and interpretation. At this writing, HER-2/neu expression should not influence the decision to use endocrine therapy.
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- 2006
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29. Lipophilic statins merit additional study for breast cancer chemoprevention.
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Prowell TM, Stearns V, and Trock B
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- Female, Humans, Randomized Controlled Trials as Topic, Breast Neoplasms prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
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- 2006
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30. What is the role of ovarian ablation in the management of primary and metastatic breast cancer today?
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Prowell TM and Davidson NE
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- Age Factors, Breast Neoplasms surgery, Chemotherapy, Adjuvant, Female, Gonadotropin-Releasing Hormone analogs & derivatives, Humans, Ovary physiology, Ovary radiation effects, Randomized Controlled Trials as Topic, Survival Analysis, Treatment Outcome, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Ovariectomy, Ovary surgery, Tamoxifen therapeutic use
- Abstract
Ovarian ablation has been used for more than a century in the treatment of breast cancer. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be accomplished medically using luteinizing hormone releasing hormone (LHRH) analogues. In addition, cytotoxic chemotherapy unpredictably produces amenorrhea and primary ovarian failure in 10%-95% of premenopausal women as a function of patient age, cumulative dose, and the specific agents used. In the metastatic setting, ovarian ablation and tamoxifen monotherapies produce comparable outcomes and may be more effective when used together. While many early adjuvant trials of ovarian ablation were methodologically flawed, a more recent meta-analysis by the Early Breast Cancer Trialists' Collaborative Group of 12 properly designed randomized trials found significantly greater disease-free and overall survival rates for women under the age of 50, regardless of nodal status, receiving ovarian ablation as a single adjuvant therapy. Several important issues regarding the role of ovarian ablation in the treatment of breast cancer remain unresolved. Data suggest that ovarian ablation followed by some years of tamoxifen produces similar results to those seen with adjuvant chemotherapy in women with hormone-receptor positive breast cancer; however, the value of combining these modalities is still unclear. Other areas of ongoing investigation include the appropriate duration of therapy with LHRH analogues in the adjuvant setting, the long-term sequelae of ovarian suppression among young breast cancer survivors, and refinement of the population most likely to benefit from ovarian ablation or suppression.
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- 2004
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