13 results on '"Symmans, W. Fraser"'
Search Results
2. A phase II study of Mirvetuximab Soravtansine in triple-negative breast cancer.
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Yam, Clinton, Rauch, Gaiane M., Rahman, Tanbin, Karuturi, Meghan, Ravenberg, Elizabeth, White, Jason, Clayborn, Alyson, McCarthy, Pamela, Abouharb, Sausan, Lim, Bora, Litton, Jennifer K., Ramirez, David L., Saleem, Sadia, Stec, James, Symmans, W. Fraser, Huo, Lei, Damodaran, Senthil, Sun, Ryan, and Moulder, Stacy L.
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THERAPEUTIC use of monoclonal antibodies ,STAINS & staining (Microscopy) ,CLINICAL trials ,IMMUNOHISTOCHEMISTRY ,METASTASIS ,MONOCLONAL antibodies ,INVESTIGATIONAL drugs ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,BREAST tumors ,PHARMACODYNAMICS - Abstract
Summary: Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data. [ABSTRACT FROM AUTHOR]
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- 2021
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3. A Targeted Next-Generation Sequencing Assay Detects a High Frequency of Therapeutically Targetable Alterations in Primary and Metastatic Breast Cancers: Implications for Clinical Practice.
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Vasan, Neil, Yelensky, Roman, Wang, Kai, Moulder, Stacy, Dzimitrowicz, Hannah, Avritscher, Rony, Wang, Baliang, Wu, Yun, Cronin, Maureen T., Palmer, Gary, Symmans, W. Fraser, Miller, Vincent A., Stephens, Philip, and Pusztai, Lajos
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BREAST tumors ,BREAST tumor treatment ,METASTASIS ,CANCER treatment ,DNA analysis ,BIOLOGICAL assay ,BIOPHYSICS ,BIOPSY ,MAMMALS ,RESEARCH methodology ,TISSUE culture ,GENOMICS ,DESCRIPTIVE statistics ,SEQUENCE analysis ,IN vitro studies ,GENETICS - Abstract
The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencing-based genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,154×. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = .24). The most common actionable alterations were in PIK3CA (n = 9, phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor receptor inhibitors). Our sequencing assay also correctly identified all six cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when tumor content was adequate. In addition, two known activating HER2 mutations were identified, both in unamplified cases. Conclusion. Overall, 84% of cancers harbored at least one genomic alteration linked to potential treatment options. Systematic evaluation of the predictive value of these genomic alterations is critically important for further progress in this field. [ABSTRACT FROM AUTHOR]
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- 2014
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4. DNA Repair Gene Patterns as Prognostic and Predictive Factors in Molecular Breast Cancer Subtypes.
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Santarpia, Libero, Iwamoto, Takayuki, Di Leo, Angelo, Hayashi, Naoki, Bottai, Giulia, Stampfer, Martha, André, Fabrice, Turner, Nicholas C., Symmans, W. Fraser, Hortobágyi, Gabriel N., Pusztai, Lajos, and Bianchini, Giampaolo
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BREAST cancer prognosis ,CANCER chemotherapy ,ANTHRACYCLINES ,BREAST tumors ,DNA ,FISHER exact test ,GENE expression ,IMMUNOHISTOCHEMISTRY ,LONGITUDINAL method ,RESEARCH funding ,T-test (Statistics) ,TUMOR markers ,PROPORTIONAL hazards models ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n=294) or anthracycline (n=210). We independently assessed estrogen receptor (ER)-positive/ HER2-negative, HER2-positive, and ER-negative/ HER2-negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty-two genes were consistently over expressed in ER-negative tumors, and five genes were over expressed in ER-positive tumors, but no differences in expression were associated with HER2 status. In ER-positive/HER2-negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment-specific manner. In ER-negative/ HER2-negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline-treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2- positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA-damaging agents. [ABSTRACT FROM AUTHOR]
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- 2013
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5. Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker.
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Saura, Cristina, Tseng, Ling‐Ming, Chan, Stephen, Chacko, Raju T., Campone, Mario, Manikhas, Alexy, Nag, Shona M., Leichman, Cynthia G., Dasappa, Lokanatha, Fasching, Peter A., Hurtado de Mendoza, Fernando, Symmans, W. Fraser, Liu, David, Mukhopadhyay, Pralay, Horak, Christine, Xing, Guan, and Pusztai, Lajos
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DOXORUBICIN ,PACLITAXEL ,MACROLIDE antibiotics ,CYCLOPHOSPHAMIDE ,ANALYSIS of variance ,BIOMARKERS ,BREAST tumors ,CONFIDENCE intervals ,DRUG side effects ,FISHER exact test ,MEDICAL cooperation ,NERVE tissue proteins ,HEALTH outcome assessment ,RESEARCH ,RESEARCH funding ,T-test (Statistics) ,LOGISTIC regression analysis ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,EARLY medical intervention ,STATISTICAL models ,DESCRIPTIVE statistics ,KARNOFSKY Performance Status ,THERAPEUTICS - Abstract
Background. This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated. Patients and Methods. Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m
2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. βIII-Tubulin expression was assessed using immunohistochemistry. Results. There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI],18.6-30.8)and the paclitaxel treatment arm (25.2%;90%CI, 19.4-31.7). βIII-Tubulin-positive patients obtained higher pCR Rates compared with βIII-tubulin-negative patients in both treatment arms; however, βIII-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy. Conclusions. Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among βIII-tubulin-positive patients. [ABSTRACT FROM AUTHOR]- Published
- 2013
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6. Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer.
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Shinde SS, Forman MR, Kuerer HM, Yan K, Peintinger F, Hunt KK, Hortobagyi GN, Pusztai L, Symmans WF, Shinde, Shivani S, Forman, Michele R, Kuerer, Henry M, Yan, Kai, Peintinger, Florentia, Hunt, Kelly K, Hortobagyi, Gabriel N, Pusztai, Lajos, and Symmans, W Fraser
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AGE distribution ,BREAST tumors ,BREASTFEEDING ,MENARCHE ,RESEARCH funding ,TIME ,PHENOTYPES ,PARITY (Obstetrics) ,HORMONE-dependent tumors - Abstract
Background: The combination of increased parity and shorter breastfeeding duration might increase the odds of the least differentiated triple-negative breast cancer (BC) phenotype, theoretically because an expanded progenitor cell population from each pregnancy would incompletely differentiate postpartum.Methods: Subjects consisted of a consecutive case series of 2473 women treated for invasive breast cancer between 2001 and 2006. Breast cancer phenotype (triple-negative BC, vs non-triple-negative BC) was compared with reproductive and demographic information. Odds ratios (OR) with 95% confidence intervals (CIs) for the association of breastfeeding duration (months per child) and parity with triple-negative BC were calculated after adjusting for ethnicity, age at menarche, family history, and age at diagnosis.Results: Compared with non-triple-negative BC, triple-negative BC was associated with shorter duration of breastfeeding per child (OR, 0.93; 95% CI, 0.90-0.97) and with higher parity (OR, 1.12; 95% CI, 1.06-1.20). By using multivariate logistic regression, triple-negative BC was independently associated with higher parity (OR, 2.76 [95% CI, 1.86-4.08] if ≥3 live births; OR, 1.89 [95% CI, 1.30-2.74] if ≤2 live births vs nulliparae), breastfeeding duration (OR, 0.55 [95% CI, 0.41-0.74] if >2 mo/child and OR, 0.58 [95% CI, 0.42-0.82] if ≤2 mo/child vs none), African American ethnicity (OR, 2.10; 95% CI, 1.52-2.92), and younger age at diagnosis (OR, 3.02 [95% CI, 2.03-4.47] if ≤40 years vs >60 years).Conclusions: Among women with invasive breast cancer, higher parity and the absence or short duration of breastfeeding were independently associated with triple-negative BC. Any duration of breastfeeding was found to be associated with lower probability of triple-negative BC, and the odds of this phenotype decreased with increasing duration of breastfeeding. [ABSTRACT FROM AUTHOR]- Published
- 2010
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7. Metastases to the Breast From Nonbreast Solid Neoplasms.
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Williams, Stephanie A., Ehlers II, Richard A., Hunt, Kelly K., Min Yi, Kuerer, Henry M., Singletary, S. Eva, Ross, Merrick I., Feig, Barry W., Symmans, W. Fraser, and Meric-Bernstam, Funda
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METASTASIS ,BREAST cancer ,CANCER pathophysiology ,CANCER patients ,TUMORS ,PATHOLOGY - Abstract
The article presents information on a study which identified the clinical characteristics and outcomes associated with metastases to the breast from nonbreast solid neoplasms to identify determinants of survival. The medical records of patients who have metastatis to the breast from nonbreast solid organ primary tumors were reviewed for clinicopathological characteristics. The determinants of survival were investigated through Kaplan-Meier analysis.
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- 2007
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8. The impact of RNA extraction method on accurate RNA sequencing from formalin-fixed paraffin-embedded tissues.
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Marczyk, Michal, Fu, Chunxiao, Lau, Rosanna, Du, Lili, Trevarton, Alexander J., Sinn, Bruno V., Gould, Rebekah E., Pusztai, Lajos, Hatzis, Christos, and Symmans, W. Fraser
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NUCLEIC acid isolation methods ,NUCLEOTIDE sequence ,GENE expression ,HORMONE therapy ,TRANSLATIONAL research ,SEQUENCE analysis ,FORMALDEHYDE ,RNA ,GENES ,GENE expression profiling ,HISTOLOGICAL techniques ,RESEARCH funding ,TISSUE fixation (Histology) ,BREAST tumors - Abstract
Background: Utilization of RNA sequencing methods to measure gene expression from archival formalin-fixed paraffin-embedded (FFPE) tumor samples in translational research and clinical trials requires reliable interpretation of the impact of pre-analytical variables on the data obtained, particularly the methods used to preserve samples and to purify RNA.Methods: Matched tissue samples from 12 breast cancers were fresh frozen (FF) and preserved in RNAlater or fixed in formalin and processed as FFPE tissue. Total RNA was extracted and purified from FF samples using the Qiagen RNeasy kit, and in duplicate from FFPE tissue sections using three different kits (Norgen, Qiagen and Roche). All RNA samples underwent whole transcriptome RNA sequencing (wtRNAseq) and targeted RNA sequencing for 31 transcripts included in a signature of sensitivity to endocrine therapy. We assessed the effect of RNA extraction kit on the reliability of gene expression levels using linear mixed-effects model analysis, concordance correlation coefficient (CCC) and differential analysis. All protein-coding genes in the wtRNAseq and three gene expression signatures for breast cancer were assessed for concordance.Results: Despite variable quality of the RNA extracted from FFPE samples by different kits, all had similar concordance of overall gene expression from wtRNAseq between matched FF and FFPE samples (median CCC 0.63-0.66) and between technical replicates (median expression difference 0.13-0.22). More than half of genes were differentially expressed between FF and FFPE, but with low fold change (median |LFC| 0.31-0.34). Two out of three breast cancer signatures studied were highly robust in all samples using any kit, whereas the third signature was similarly discordant irrespective of the kit used. The targeted RNAseq assay was concordant between FFPE and FF samples using any of the kits (CCC 0.91-0.96).Conclusions: The selection of kit to purify RNA from FFPE did not influence the overall quality of results from wtRNAseq, thus variable reproducibility of gene signatures probably relates to the reliability of individual gene selected and possibly to the algorithm. Targeted RNAseq showed promising performance for clinical deployment of quantitative assays in breast cancer from FFPE samples, although numerical scores were not identical to those from wtRNAseq and would require calibration. [ABSTRACT FROM AUTHOR]- Published
- 2019
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9. Breast Cancer Genomics: Challenges in Interpretation and Application.
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Kelly, Cathy M., Symmans, W. Fraser, Andreopoulou, Eleni, and Bianchini, Giampaolo
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BREAST tumors ,BREAST tumor treatment ,BREAST cancer prognosis ,DNA analysis ,TIME ,TUMOR classification ,GENETIC testing ,GENETICS - Abstract
The article discusses the problems of over-fitting and multiple testing in breast cancer genomics and the resultant exponential increase in statistical interactions, challenges in interpretation and application. The study covers key areas including influence of time-dependent variables, chemosensitivity, endocrine sensitivity, and sequential synergy. The article concludes that appropriate statistical rigour must be ensured for correct interpretation of gene expression profile results.
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- 2013
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10. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial.
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Hurvitz, Sara A, Martin, Miguel, Symmans, W Fraser, Jung, Kyung Hae, Huang, Chiun-Sheng, Thompson, Alastair M, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Beckmann, Matthias W, Afenjar, Karen, Fresco, Rodrigo, Helms, Hans-Joachim, Xu, Jin, Lin, Yvonne G, Sparano, Joseph, and Slamon, Dennis
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HORMONE receptor positive breast cancer , *TRASTUZUMAB , *CANCER chemotherapy , *CANCER relapse , *DOCETAXEL , *CARBOPLATIN , *CANCER treatment , *ANTINEOPLASTIC agents , *BREAST tumors , *CELL receptors , *COMBINED modality therapy , *COMPARATIVE studies , *HYDROCARBONS , *RESEARCH methodology , *MEDICAL cooperation , *MONOCLONAL antibodies , *RESEARCH , *RESEARCH funding , *STATISTICAL sampling , *TIME , *TUMOR classification , *EVALUATION research , *RANDOMIZED controlled trials , *TREATMENT effectiveness - Abstract
Background: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.Methods: We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.Findings: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment.Interpretation: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.Funding: F Hoffmann-La Roche and Genentech. [ABSTRACT FROM AUTHOR]- Published
- 2018
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11. Standardizing Pathologic Evaluation of Breast Carcinoma After Neoadjuvant Chemotherapy.
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Sunati Sahoo, Krings, Gregor, Yunn-Yi Chen, Carter, Jodi M., Beiyun Chen, Hua Guo, Hanina Hibshoosh, Reisenbichler, Emily, Fang Fan, Shi Wei, Khazai, Laila, Balassanian, Ronald, Klein, Molly E., Shad, Sonal, Venters, Sara J., Borowsky, Alexander D., Symmans, W. Fraser, and Tolgay Ocal, I.
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BREAST cancer prognosis , *ADJUVANT chemotherapy , *CLINICAL pathology , *SENTINEL lymph node biopsy , *CANCER patients , *TREATMENT effectiveness , *MEDICAL protocols , *TUMOR classification , *CELL proliferation , *COMBINED modality therapy , *TUMOR markers , *COLLECTION & preservation of biological specimens , *PREDICTION models , *PROGRESSION-free survival , *BREAST tumors , *NEEDLE biopsy , *EVALUATION - Abstract
Context.-- Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.-- To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data sources.-- English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.-- This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
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Loibl, Sibylle, O'Shaughnessy, Joyce, Untch, Michael, Sikov, William M, Rugo, Hope S, McKee, Mark D, Huober, Jens, Golshan, Mehra, von Minckwitz, Gunter, Maag, David, Sullivan, Danielle, Wolmark, Norman, McIntyre, Kristi, Ponce Lorenzo, Jose J, Metzger Filho, Otto, Rastogi, Priya, Symmans, W Fraser, Liu, Xuan, JrGeyer, Charles E, and O'Shaughnessy, Joyce
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BREAST cancer , *CARBOPLATIN , *CANCER chemotherapy , *RETINOBLASTOMA , *CLINICAL trials , *ANEMIA , *ANTHROPOMETRY , *ANTINEOPLASTIC agents , *BREAST tumors , *COMBINED modality therapy , *COMPARATIVE studies , *DOXORUBICIN , *SURGICAL excision , *HETEROCYCLIC compounds , *LYMPH nodes , *LYMPH node surgery , *MASTECTOMY , *RESEARCH methodology , *MEDICAL cooperation , *METASTASIS , *GENETIC mutation , *PACLITAXEL , *PROGNOSIS , *RESEARCH , *STATISTICAL sampling , *SURVIVAL , *THROMBOCYTOPENIA , *EVALUATION research , *RANDOMIZED controlled trials , *BRCA genes , *TREATMENT effectiveness , *BLIND experiment , *CYCLOPHOSPHAMIDE - Abstract
Background: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer.Methods: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277.Findings: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]).Interpretation: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer.Funding: AbbVie. [ABSTRACT FROM AUTHOR]- Published
- 2018
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13. Axillary ultrasound during neoadjuvant systemic therapy in triple-negative breast cancer patients.
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Candelaria, Rosalind P., Adrada, Beatriz E., Hess, Kenneth, Santiago, Lumarie, Lane, Deanna L., Thompson, Alastair M., Moulder, Stacy L., Huang, Monica L., Arribas, Elsa M., Rauch, Gaiane M., Leung, Jessica W.T., Symmans, W. Fraser, Valero, Vicente, Ravenberg, Elizabeth E., White, Jason B., and Yang, Wei Tse
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AXILLARY lymph node dissection , *SENTINEL lymph node biopsy , *TRIPLE-negative breast cancer , *MICROMETASTASIS , *CANCER patients , *SENTINEL lymph nodes , *PATHOLOGY , *SURGICAL pathology , *BREAST tumor treatment , *ULTRASONIC imaging , *AXILLA , *LYMPH nodes , *RESEARCH funding , *COMBINED modality therapy , *BREAST tumors , *LONGITUDINAL method - Abstract
Purpose: To investigate the value of performing mid-treatment axillary ultrasound (AUS) in triple-negative breast cancer (TNBC) patients who are undergoing neoadjuvant systemic therapy (NAST) by determining the optimal cutoff number of abnormal nodes associated with residual nodal disease on surgical pathology.Materials and Methods: This sub-study, an interim analysis of an ongoing single-institution clinical trial enrolling patients with stage I-III TNBC, included 106 patients. Number of abnormal nodes at mid-treatment was assessed and recorded by experienced breast radiologists, who empirically categorized lymph nodes using a binary approach of sonographically-normal versus abnormal. Pathologic lymph node positivity was defined as presence of macrometastasis or micrometastasis in ≥1 axillary node from sentinel lymph node biopsy and/or axillary lymph node dissection.Results: Of 106 patients, 26 (25 %) had residual nodal disease and 80 (75 %) had no nodal disease at surgery. Median number of abnormal nodes at mid-treatment was 5 (standard deviation [SD], 5) for patients with residual nodal disease and 0 (SD, 2) for patients with no nodal disease at surgery (p < 0.0001). TNBC patients with >4 abnormal nodes at mid-treatment had a significantly higher chance of being node-positive at surgery (AUC = 0.908, p < 0.0001; PPV = 90 %).Conclusion: Our data suggest that a cutoff of >4 abnormal nodes on mid-treatment AUS is associated with residual disease post-NAST. If our findings are substantiated by subsequent analyses, then mid-treatment AUS could be used to identify patients unlikely to achieve nodal pathologic complete response and who should be offered alternative therapy. [ABSTRACT FROM AUTHOR]- Published
- 2020
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