23 results on '"Symmans, W. Fraser"'
Search Results
2. Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.
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Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, and Pusztai L
- Abstract
Purpose: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC., Patients and Methods: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC., Results: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates ( P < .0001) and 3-year overall survival (OS) rates ( P < .0001). TNBC was associated with increased risk for visceral metastases ( P = .0005), lower risk for bone recurrence ( P = .027), and shorter postrecurrence survival ( P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival ( P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC ( P < .0001)., Conclusion: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.
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- 2023
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3. Evaluation of the Sensitivity to Endocrine Therapy Index and 21-Gene Breast Recurrence Score in the SWOG S8814 Trial.
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Speers CW, Symmans WF, Barlow WE, Trevarton A, The S, Du L, Rae JM, Shak S, Baehner R, Sharma P, Pusztai L, Hortobagyi GN, Hayes DF, Albain KS, Godwin A, and Thompson A
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- Humans, Female, Retrospective Studies, Breast pathology, Tamoxifen therapeutic use, Prognosis, Chemotherapy, Adjuvant methods, Antibiotics, Antineoplastic therapeutic use, Anthracyclines therapeutic use, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Purpose: Chemotherapy has not demonstrated benefit over adjuvant endocrine therapy alone for postmenopausal patients with node-positive breast cancer with a 21-gene breast recurrence score (RS) of 25 or below (RS ≤ 25). We tested whether combined results from RS and the sensitivity to endocrine therapy (SET2,3) index of endocrine-related transcription (SET
ER/PR ) adjusted for baseline prognostic index (BPI) improve prognostic assessment, and whether SET2,3 predicted benefit from anthracycline-based chemotherapy., Methods: A blinded retrospective clinical validation of SET2,3 in two randomized treatment arms from the SWOG S8814 trial comparing adjuvant anthracycline-based chemotherapy followed by tamoxifen endocrine therapy for 5 years, versus tamoxifen alone. SET2,3 assay was calibrated and measured using whole-transcriptome RNA sequence of tumor samples already tested for RS. The primary end point was disease-free survival (DFS)., Results: There were 106 events in 283 patients over a median follow-up of 8.99 years. Proportional hazards assumptions were met during the first 5 years only. SET2,3 index and RS were not correlated (r = -0.04) and were independently prognostic (SET2,3: hazard ratio [HR], 0.48 per unit; 95% CI, 0.34 to 0.68; P < .001; RS: HR, 1.28 per 10 units; 95% CI, 1.14 to 1.44; P < .001). SET2,3 index did not predict chemotherapy benefit (interaction P = .77). SET2,3 was high in 93/175 (53%) patients with RS ≤ 25 (concordant low-risk), with 5-year DFS 97%. SET2,3 was low in 55/108 (51%) patients with RS > 25 (concordant high-risk), with 5-year DFS 53%. Both components of SET2,3 index were prognostic after adjustment for RS: SETER/PR (HR, 0.65; 95% CI, 0.46 to 0.92) and BPI (HR, 0.45; 95% CI, 0.31 to 0.64)., Conclusion: SET2,3 index was not correlated with RS, demonstrated additive prognostic performance, and was not chemopredictive in this subset of patients from S8814. The SETER/PR and BPI components of SET2,3 each added prognostic information to RS.- Published
- 2023
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4. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline.
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Korde LA, Somerfield MR, Carey LA, Crews JR, Denduluri N, Hwang ES, Khan SA, Loibl S, Morris EA, Perez A, Regan MM, Spears PA, Sudheendra PK, Symmans WF, Yung RL, Harvey BE, and Hershman DL
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- Biomarkers, Tumor antagonists & inhibitors, Breast Neoplasms metabolism, Breast Neoplasms pathology, Female, Humans, Prognosis, Systematic Reviews as Topic, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms drug therapy, Molecular Targeted Therapy methods, Neoadjuvant Therapy methods, Practice Guidelines as Topic standards, Receptor, ErbB-2 metabolism
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Purpose: To develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer., Methods: ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options., Results: A total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations., Recommendations: Patients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy.Additional information is available at www.asco.org/breast-cancer-guidelines., Competing Interests: Reprint Requests: 2318 Mill Road, Suite 800, Alexandria, VA 22314; guidelines@asco.org Lisa A. CareyResearch Funding: Innocrin Pharma, Syndax, Immunomedics, Novartis, NanoString Technologies, AbbVie, Seattle GeneticsPatents, Royalties, Other Intellectual Property: Royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme(OPTIONAL) Uncompensated Relationships: Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, Exact Sciences, AstraZeneca/Daiichi Sanyo, Aptitude Health(OPTIONAL) Open Payments Link: https://openpaymentsdata.cms.gov/physician/179671 Neelima DenduluriResearch Funding: Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, ImmunomedicsTravel, Accommodations, Expenses: Seattle Genetics Sibylle LoiblHonoraria: Chugai PharmaConsulting or Advisory Role: Pfizer, Roche, Novartis, Seattle Genetics, Celgene, Lilly, AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck KGaA, AbbVie, Amgen, prime/Medscape, Daiichi Sankyo, Samsung, Puma Biotechnology, Pierre Fabre, Immunomedics, GlaxoSmithKline, EirGenix, BayerResearch Funding: AbbVie, AstraZeneca, Vifor Pharma, Amgen, Celgene, Novartis, Pfizer, Roche, Cepheid, Myriad Genetics, Immunomedics, Seattle Genetics, Daiichi Sankyo, Pierre FabrePatents, Royalties, Other Intellectual Property: Patent Pending EP14153692.0 Elizabeth A. MorrisResearch Funding: GRAIL Alejandra PerezResearch Funding: Genentech/Roche, Macrogenics, Nektar, Immunomedics, AstraZeneca Meredith M. ReganHonoraria: Bristol-Myers SquibbConsulting or Advisory Role: Ipsen, Tolmar, Bristol-Myers SquibbResearch Funding: Veridex, OncoGenex, Pfizer, Ipsen, Novartis, Merck, Ferring, Celgene, AstraZeneca, Pierre Fabre, Ipsen, Bayer, Bristol-Myers Squibb, Roche, Astellas Pharma, Medivation, Janssen, Millennium Pharamceuticals, Sanofi, Sotio, Dendreon, Pfizer, TerSeraTravel, Accommodations, Expenses: Bristol-Myers Squibb Patricia A. SpearsConsulting or Advisory Role: Pfizer Preeti K. SudheendraHonoraria: Boston ScientificConsulting or Advisory Role: Boston Scientific, Vesper Medical, Sirtex MedicalSpeakers' Bureau: Boston Scientific W. Fraser SymmansStock and Other Ownership Interests: ISIS Pharmaceuticals, Nuvera Biosciences, Delphi Diagnostics, Eiger BioPharmaceuticalsConsulting or Advisory Role: Merck, Almac DiagnosticsPatents, Royalties, Other Intellectual Property: Intellectual propertyTravel, Accommodations, Expenses: Luminex, Merck(OPTIONAL) Uncompensated Relationships: Delphi Diagnostics Rachel L. YungResearch Funding: Novartis, Odonate Therapeutics Dawn L. HershmanConsulting or Advisory Role: AIM Specialty HealthNo other potential conflicts of interest were reported.
- Published
- 2021
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5. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update.
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Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, Hayes DF, Lakhani SR, Chavez-MacGregor M, Perlmutter J, Perou CM, Regan MM, Rimm DL, Symmans WF, Torlakovic EE, Varella L, Viale G, Weisberg TF, McShane LM, and Wolff AC
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- Female, Humans, Immunohistochemistry methods, Immunohistochemistry standards, Systematic Reviews as Topic, Breast Neoplasms chemistry, Breast Neoplasms metabolism, Receptors, Estrogen analysis, Receptors, Estrogen metabolism, Receptors, Progesterone analysis, Receptors, Progesterone metabolism
- Abstract
Purpose: To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline., Methods: A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature., Recommendations: The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.
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- 2020
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6. MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.
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Chien AJ, Tripathy D, Albain KS, Symmans WF, Rugo HS, Melisko ME, Wallace AM, Schwab R, Helsten T, Forero-Torres A, Stringer-Reasor E, Ellis ED, Kaplan HG, Nanda R, Jaskowiak N, Murthy R, Godellas C, Boughey JC, Elias AD, Haley BB, Kemmer K, Isaacs C, Clark AS, Lang JE, Lu J, Korde L, Edmiston KK, Northfelt DW, Viscusi RK, Yee D, Perlmutter J, Hylton NM, Van't Veer LJ, DeMichele A, Wilson A, Peterson G, Buxton MB, Paoloni M, Clennell J, Berry S, Matthews JB, Steeg K, Singhrao R, Hirst GL, Sanil A, Yau C, Asare SM, Berry DA, and Esserman LJ
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms enzymology, Breast Neoplasms surgery, Doxorubicin administration & dosage, Doxorubicin adverse effects, Female, Heterocyclic Compounds, 3-Ring administration & dosage, Humans, Middle Aged, Neoadjuvant Therapy, Paclitaxel administration & dosage, Paclitaxel adverse effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Receptors, Steroid metabolism, Trastuzumab administration & dosage, Trastuzumab adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Receptor, ErbB-2 biosynthesis
- Abstract
Purpose: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer., Patients and Methods: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week., Results: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform)., Conclusion: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
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- 2020
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7. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.
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Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Fasching PA, Afenjar K, Spera G, Lopez-Valverde V, Song C, Trask P, Boulet T, Sparano JA, Symmans WF, Thompson AM, and Slamon D
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- Adult, Aged, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carboplatin administration & dosage, Chemotherapy, Adjuvant, Disease-Free Survival, Docetaxel administration & dosage, Female, Humans, Kaplan-Meier Estimate, Middle Aged, Neoadjuvant Therapy, Trastuzumab administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Receptor, ErbB-2 metabolism
- Abstract
Purpose: The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE., Methods: Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery)., Results: Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment., Conclusion: Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.
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- 2019
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8. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype.
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Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, Walls A, Bousamra A, Ramineni M, Sinn B, Hunt K, Buchholz TA, Valero V, Buzdar AU, Yang W, Brewster AM, Moulder S, Pusztai L, Hatzis C, and Hortobagyi GN
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- Breast Neoplasms chemistry, Chemotherapy, Adjuvant, Cyclophosphamide administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Epirubicin administration & dosage, Female, Fluorouracil administration & dosage, Humans, Middle Aged, Neoadjuvant Therapy, Neoplasm, Residual, Paclitaxel administration & dosage, Phenotype, Prognosis, Prospective Studies, Risk Assessment, Survival Rate, Time Factors, Trastuzumab administration & dosage, Tumor Burden, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Receptors, Progesterone analysis
- Abstract
Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.
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- 2017
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9. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry.
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Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, Ueno NT, Zhang J, Shi W, Qi Y, Matsuoka J, Yang EJ, Hortobagyi GN, Hatzis C, Symmans WF, and Pusztai L
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- Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Estrogen Receptor alpha biosynthesis, Estrogen Receptor alpha metabolism, Female, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, RNA, Messenger biosynthesis, Randomized Controlled Trials as Topic, Breast Neoplasms genetics, Estrogen Receptor alpha genetics, RNA, Messenger genetics
- Abstract
Purpose: We examined borderline estrogen receptor (ER) -positive cancers, defined as having 1% to 10% positivity by immunohistochemistry (IHC), to determine whether they show the same global gene-expression pattern and high ESR1 mRNA expression as ER-positive cancers or if they are more similar to ER-negative cancers., Patients and Methods: ER status was determined by IHC in 465 primary breast cancers and with the Affymetrix U133A gene chip. We compared expressions of ESR1 mRNA and a 106 probe set ER-associated gene signature score between ER-negative (n = 183), 1% to 9% (n = 25), 10% (n = 6), and more than 10% (n = 251) ER-positive cancers. We also assessed the molecular class by using the PAM50 classifier and plotted survival by ER status., Results: Among the 1% to 9%, 10%, and more than 10% ER IHC-positive patients, 24%, 67%, and 92% were also positive by ESR1 mRNA expression. The average ESR1 expression was significantly higher in the ≥ 10% ER-positive cohorts compared with the 1% to 9% or ER-negative cohort. The average ER gene signature scores were similar for the ER-negative and 1% to 9% IHC-positive patients and were significantly lower than in ≥ 10% ER-positive patients. Among the 1% to 9% ER-positive patients, 8% were luminal B and 48% were basal-like; among the 10% ER-positive patients, 50% were luminal. The overall survival rate of 1% to 9% ER-positive patients with cancer was between those of patients in the ≥ 10% ER-positive and ER-negative groups., Conclusion: A minority of the 1% to 9% IHC ER-positive tumors show molecular features similar to those of ER-positive, potentially endocrine-sensitive tumors, whereas most show ER-negative, basal-like molecular characteristics. The safest clinical approach may be to use both adjuvant endocrine therapy and chemotherapy in this rare subset of patients.
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- 2012
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10. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers.
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Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L, Hatzis C, Hortobagyi GN, Andre F, Gianni L, Symmans WF, and Pusztai L
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- Amyloid beta-Protein Precursor genetics, Antineoplastic Agents, Hormonal therapeutic use, B-Lymphocytes pathology, Biopsy, Fine-Needle, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Chi-Square Distribution, Collagen Type IV genetics, Extracellular Matrix Proteins, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Metagenome genetics, Neoplasm Recurrence, Local, Phospholipid Transfer Proteins genetics, Prognosis, Proportional Hazards Models, Prospective Studies, Protease Nexins, Protein Serine-Threonine Kinases genetics, Receptor, Transforming Growth Factor-beta Type II, Receptors, Cell Surface genetics, Receptors, Transforming Growth Factor beta genetics, Survival Analysis, Tamoxifen therapeutic use, Breast Neoplasms genetics, Receptors, Estrogen genetics
- Abstract
Purpose: The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers., Methods: We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients., Results: We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value., Conclusion: Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.
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- 2010
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11. Genomic index of sensitivity to endocrine therapy for breast cancer.
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Symmans WF, Hatzis C, Sotiriou C, Andre F, Peintinger F, Regitnig P, Daxenbichler G, Desmedt C, Domont J, Marth C, Delaloge S, Bauernhofer T, Valero V, Booser DJ, Hortobagyi GN, and Pusztai L
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- Aromatase Inhibitors therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms mortality, Breast Neoplasms secondary, Chemotherapy, Adjuvant, Chi-Square Distribution, Disease-Free Survival, Estrogen Receptor alpha metabolism, Female, Gene Expression Profiling, Humans, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Patient Selection, Proportional Hazards Models, Risk Assessment, Risk Factors, Survival Analysis, Tamoxifen therapeutic use, Time Factors, Transcription, Genetic, Treatment Outcome, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Estrogen Receptor alpha genetics, Gene Expression Regulation, Neoplastic, Genomics methods
- Abstract
Purpose: We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy., Methods: A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively)., Results: The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET., Conclusion: The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.
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- 2010
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12. Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer.
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Caudle AS, Gonzalez-Angulo AM, Hunt KK, Liu P, Pusztai L, Symmans WF, Kuerer HM, Mittendorf EA, Hortobagyi GN, and Meric-Bernstam F
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- Adult, Aged, Aged, 80 and over, Anthracyclines administration & dosage, Bridged-Ring Compounds administration & dosage, Carcinoma, Ductal, Breast diagnosis, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Lobular diagnosis, Carcinoma, Lobular drug therapy, Chemotherapy, Adjuvant, Disease Progression, Female, Humans, Middle Aged, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Survival Rate, Taxoids administration & dosage, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms diagnosis, Breast Neoplasms drug therapy, Neoadjuvant Therapy
- Abstract
PURPOSE Although most breast cancer patients who receive neoadjuvant chemotherapy (NCT) have a tumor response, a small proportion experience progressive disease (PD). Predictors of response have been reported, but predictors for progression have not been identified. We sought to identify predictors of tumor progression during NCT with the ultimate aim of identifying patients who might benefit from a first-line surgical approach or from novel targeted therapies. PATIENTS AND METHODS Data were obtained from reviewing medical records of patients with stage I to III breast cancer who received NCT (anthracycline and/or taxane based). Statistical analysis was performed to compare patients with any response or stable disease with patients with PD. RESULTS One thousand nine hundred twenty-eight patients received NCT; 1,762 patients (91%) had some response, 107 (6%) had stable disease, and 59 (3%) had PD at some point during NCT. Factors predictive of PD included African American race (P = .002), tumor (T) status (P = .002), and American Joint Committee on Cancer clinical stage (P = .02). Histopathologic features of PD were high tumor grade (P = .005), high Ki-67 score (P = .002), and negative estrogen receptor (ER)/progesterone receptor (PR) status (P < .001/P < .001). Pre-NCT T status, race, and ER status were independent predictors of progression in multivariate analysis. Disease progression was a negative predictor of distant disease-free survival and overall survival in multivariate analysis (P < .001). CONCLUSION Factors predictive of PD include race, advanced tumor stage, high nuclear grade, high Ki-67 score, and ER/PR negativity. Because many of these variables are also associated with response to NCT, novel molecular predictors are needed to identify patients at risk for progression on standard NCT.
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- 2010
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13. Evaluation of microtubule-associated protein-Tau expression as a prognostic and predictive marker in the NSABP-B 28 randomized clinical trial.
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Pusztai L, Jeong JH, Gong Y, Ross JS, Kim C, Paik S, Rouzier R, Andre F, Hortobagyi GN, Wolmark N, and Symmans WF
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- Anthracyclines administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Chemotherapy, Adjuvant, Cyclophosphamide adverse effects, Doxorubicin adverse effects, Estrogen Receptor alpha metabolism, Female, Follow-Up Studies, Humans, Immunohistochemistry statistics & numerical data, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Paclitaxel adverse effects, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Receptor, ErbB-2 metabolism, Biomarkers, Tumor biosynthesis, Microtubule-Associated Proteins biosynthesis, tau Proteins biosynthesis
- Abstract
Purpose: We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project (NSABP) -B 28 clinical trial. Expression levels were correlated with disease-free survival (DFS) and overall survival (OS). Interaction between this marker and paclitaxel efficacy was also examined., Methods: Tissue microarrays were available for 1,942 patients (63% of all trial participants) who were randomly assigned to receive either four courses of doxorubicin and cyclophosphamide (AC) or AC followed by four courses of adjuvant paclitaxel chemotherapy. All patients who were hormone receptor positive received adjuvant endocrine therapy. Immunohistochemistry was used to measure Tau expression at M. D. Anderson Cancer Center blinded to clinical outcome. Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center., Results: Forty-three percent of patients were Tau positive. Tau positivity correlated with estrogen receptor (ER) -positive status (P < .0001), lower histologic grade (P < .001), and lack of human epidermal growth factor receptor 2 (HER2) expression (P < .0001). In univariate analyses, Tau- and ER-positive status were both associated with better DFS and OS (P < .0001) whereas greater tumor size, high grade, lymph node- and HER2-positive status were each associated with worse DFS and OS (P < .0001). In multivariate analysis, the same variables except HER2 remained significant. There was no significant interaction between Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients., Conclusion: High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy, but there was no significant interaction between Tau expression and paclitaxel benefit.
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- 2009
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14. Ductal carcinoma in situ: state of the science and roadmap to advance the field.
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Kuerer HM, Albarracin CT, Yang WT, Cardiff RD, Brewster AM, Symmans WF, Hylton NM, Middleton LP, Krishnamurthy S, Perkins GH, Babiera G, Edgerton ME, Czerniecki BJ, Arun BK, and Hortobagyi GN
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms therapy, Carcinoma in Situ genetics, Carcinoma in Situ metabolism, Carcinoma in Situ therapy, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast therapy, Female, Humans, Breast Neoplasms pathology, Carcinoma in Situ pathology, Carcinoma, Ductal, Breast pathology
- Abstract
Purpose: Ductal carcinoma in situ (DCIS) is the fourth leading cancer for women in the United States. Understanding of the biology and clinical behavior of DCIS is imperfect. This article highlights the current knowledge base and the scientific roadmap needed to advance the field., Methods: This article is based on work done by and consultations obtained from leading experts in the field over a 6-month period that culminated in a full-day symposium designed to systematically review the most pertinent MEDLINE published reports and develop a roadmap to elucidate the molecular steps of carcinogenesis, reduce the extent or prevent the need for therapies, eliminate recurrences, and reduce morbidity., Results: Expression profiling of pure DCIS will help elucidate the molecular characteristics that distinguish high-risk lesions from clinically irrelevant lesions. The development of new methods of extracting RNA from processed tissues may provide opportunities for research. Mammography often underestimates the pathologic extent of DCIS; other imaging methods need to be investigated for detection and monitoring of disease stability or progression. Novel biologic agents are being delivered in neoadjuvant clinical trials, and alternative methods for breast irradiation are being studied. Future trials of treatment versus no treatment for biologically selected cases of DCIS should be developed., Conclusion: There is a critical need for a concerted international effort among patients with DCIS, clinicians, and basic scientists to conduct the research necessary to improve fundamental understanding of the biology and clinical behavior of DCIS and prevent development of invasive breast cancer.
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- 2009
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15. Effect of molecular disease subsets on disease-free survival in randomized adjuvant chemotherapy trials for estrogen receptor-positive breast cancer.
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Pusztai L, Broglio K, Andre F, Symmans WF, Hess KR, and Hortobagyi GN
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- Chemotherapy, Adjuvant, Disease-Free Survival, Female, Humans, Randomized Controlled Trials as Topic, Receptors, Estrogen, Risk Assessment, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Research Design
- Abstract
Purpose: The majority of estrogen receptor (ER)-positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy., Methods: We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study., Results: The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%., Conclusion: Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.
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- 2008
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16. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.
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Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, and Pusztai L
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Chemotherapy, Adjuvant, Female, Humans, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Neoplasm, Residual drug therapy, Neoplasm, Residual metabolism, Neoplasm, Residual pathology, Neoplasms, Hormone-Dependent drug therapy, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Prognosis, Prospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Neoadjuvant Therapy, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism
- Abstract
Purpose: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC., Patients and Methods: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC., Results: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001)., Conclusion: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.
- Published
- 2008
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17. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy.
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Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, and Pusztai L
- Subjects
- Axilla, Disease-Free Survival, Female, Humans, Lymphatic Metastasis pathology, Middle Aged, Multivariate Analysis, Neoadjuvant Therapy, Predictive Value of Tests, Proportional Hazards Models, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Neoplasm, Residual pathology
- Abstract
Purpose: To measure residual disease after neoadjuvant chemotherapy in order to improve the prognostic information that can be obtained from evaluating pathologic response., Patients and Methods: Pathologic slides and reports were reviewed from 382 patients in two different treatment cohorts: sequential paclitaxel (T) then fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 241 patients; and a single regimen of FAC in 141 patients. Residual cancer burden (RCB) was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses., Results: RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pathologic complete response [pCR] v residual disease [RD]; hazard ratio = 2.50; 95% CI 1.70 to 3.69; P < .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort., Conclusion: RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance.
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- 2007
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18. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome.
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Mazouni C, Peintinger F, Wan-Kau S, Andre F, Gonzalez-Angulo AM, Symmans WF, Meric-Bernstam F, Valero V, Hortobagyi GN, and Pusztai L
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Invasiveness, Recurrence, Retrospective Studies, Treatment Outcome, Breast Neoplasms pathology, Breast Neoplasms therapy, Carcinoma, Intraductal, Noninfiltrating pathology, Carcinoma, Intraductal, Noninfiltrating therapy, Neoadjuvant Therapy methods, Neoplasm, Residual pathology
- Abstract
Purpose: To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer., Patients and Methods: Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS)., Results: The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63)., Conclusion: Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.
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- 2007
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19. Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.
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Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, Rouzier R, Sneige N, Ross JS, Vidaurre T, Gómez HL, Hortobagyi GN, and Pusztai L
- Subjects
- Adult, Aged, Breast Neoplasms pathology, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Female, Fluorouracil administration & dosage, Gene Expression Profiling, Humans, Microarray Analysis, Middle Aged, Neoplasm Staging, Oligonucleotides, Paclitaxel administration & dosage, Predictive Value of Tests, ROC Curve, Reproducibility of Results, Sensitivity and Specificity, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Gene Expression Regulation, Neoplastic
- Abstract
Purpose: We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases., Patients and Methods: One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases., Results: Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant., Conclusion: A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).
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- 2006
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20. Nomograms to predict pathologic complete response and metastasis-free survival after preoperative chemotherapy for breast cancer.
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Rouzier R, Pusztai L, Delaloge S, Gonzalez-Angulo AM, Andre F, Hess KR, Buzdar AU, Garbay JR, Spielmann M, Mathieu MC, Symmans WF, Wagner P, Atallah D, Valero V, Berry DA, and Hortobagyi GN
- Subjects
- Anthracyclines administration & dosage, Antibiotics, Antineoplastic administration & dosage, Breast Neoplasms epidemiology, Chemotherapy, Adjuvant, Decision Making, Computer-Assisted, Disease-Free Survival, Female, France epidemiology, Humans, Internet, Logistic Models, Middle Aged, Multivariate Analysis, Neoadjuvant Therapy, Paclitaxel administration & dosage, Predictive Value of Tests, Proportional Hazards Models, Reproducibility of Results, Texas epidemiology, Anthracyclines therapeutic use, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Nomograms
- Abstract
Purpose: To combine clinical variables associated with pathologic complete response (pCR) and distant metastasis-free survival (DMFS) after preoperative chemotherapy (PC) into a prediction nomogram., Patients and Methods: Data from 496 patients treated with anthracycline PC at the Institut Gustave Roussy were used to develop and calibrate a nomogram for pCR based on multivariate logistic regression. This nomogram was tested on two independent cohorts of patients treated at the M.D. Anderson Cancer Center. The first cohort (n = 337) received anthracycline; the second cohort (n = 237) received a combination of paclitaxel and anthracycline PC. A separate nomogram to predict DMFS was developed using Cox proportional hazards regression model., Results: The pCR nomogram based on clinical stage, estrogen receptor status, histologic grade, and number of preoperative chemotherapy cycles had good discrimination and calibration in the training and the anthracycline-treated validation sets (concordance indices, 0.77, 0.79). In the paclitaxel plus anthracycline group, when the predicted pCR rate was less than 14%, the observed rate was 7.5%; for a predicted rate of > or = 38%, the actual rate was 85%. For a predicted rate between 14% to 38%, the observed rates were 50% with weekly and 27% with 3-weekly paclitaxel. This indicates that patients with intermediate chemotherapy sensitivity benefit the most from the optimized schedule of paclitaxel. Patients unlikely to achieve pCR to anthracylines remain at low probability for pCR, even after inclusion of paclitaxel. The nomogram for DMFS had a concordance index of 0.72 in the validation set and outperformed other prediction tools (P = .02)., Conclusion: Our nomograms predict pCR accurately and can serve as a basis to integrate future molecular markers into a clinical prediction model.
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- 2005
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21. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.
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Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, Mariani G, Rodriguez J, Carcangiu M, Watson D, Valagussa P, Rouzier R, Symmans WF, Ross JS, Hortobagyi GN, Pusztai L, and Shak S
- Subjects
- Adult, Aged, Biopsy, Needle, Breast Neoplasms pathology, Doxorubicin therapeutic use, Female, Gene Expression Profiling, Humans, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Paclitaxel therapeutic use, Predictive Value of Tests, Remission Induction, Reverse Transcriptase Polymerase Chain Reaction, Antineoplastic Agents therapeutic use, Breast pathology, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
Purpose: We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk., Methods: Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays., Results: Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit., Conclusion: Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.
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- 2005
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22. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks.
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Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL, Carter C, Frye D, Hunt KK, Symmans WF, Strom EA, Sahin AA, Sikov W, and Hortobagyi GN
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms pathology, Breast Neoplasms surgery, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Drug Administration Schedule, Female, Fluorouracil administration & dosage, Humans, Middle Aged, Neoplasm Invasiveness, Treatment Outcome, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Paclitaxel administration & dosage, Paclitaxel therapeutic use
- Abstract
Purpose: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST)., Patients and Methods: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy., Results: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05)., Conclusion: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.
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- 2005
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23. Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer.
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Pusztai L, Zhen JH, Arun B, Rivera E, Whitehead C, Thompson WJ, Nealy KM, Gibbs A, Symmans WF, Esteva FJ, Booser D, Murray JL, Valero V, Smith TL, and Hortobagyi GN
- Subjects
- 3',5'-Cyclic-GMP Phosphodiesterases, Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms chemistry, Breast Neoplasms pathology, Capecitabine, Cyclic Nucleotide Phosphodiesterases, Type 2, Cyclic Nucleotide Phosphodiesterases, Type 5, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Female, Fluorouracil analogs & derivatives, Humans, Immunohistochemistry, Middle Aged, Neoplasm Metastasis, Phosphoric Diester Hydrolases analysis, Prodrugs administration & dosage, Prodrugs adverse effects, Sulindac administration & dosage, Sulindac adverse effects, Sulindac analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Deoxycytidine analogs & derivatives
- Abstract
Purpose: We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC)., Patients and Methods: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing., Results: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity., Conclusion: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.
- Published
- 2003
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