21 results on '"Tung NM"'
Search Results
2. Abstract PD1-05: Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer
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Jeselsohn, R, primary, Guo, H, additional, Rees, R, additional, Barry, WT, additional, Barlett, CH, additional, Tung, NM, additional, Krop, IE, additional, Brown, M, additional, and Winer, EP, additional
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- 2019
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3. P3-16-05: A Phase II Trial Expansion Cohort of the PARP Inhibitor Veliparib (ABT888) and Temozolomide in BRCA1/2 Associated Metastatic Breast Cancer.
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Isakoff, SJ, primary, Overmoyer, B, additional, Tung, NM, additional, Gelman, RS, additional, Habin, K, additional, Qian, J, additional, Giranda, V, additional, Shepherd, S, additional, Garber, JE, additional, Ellisen, LW, additional, Winer, EP, additional, and Goss, PE, additional
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- 2011
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4. Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer.
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Villacampa G, Tung NM, Pernas S, Paré L, Bueno-Muiño C, Echavarría I, López-Tarruella S, Roche-Molina M, Del Monte-Millán M, Marín-Aguilera M, Brasó-Maristany F, Waks AG, Pascual T, Martínez-Sáez O, Vivancos A, Conte PF, Guarneri V, Vittoria Dieci M, Griguolo G, Cortés J, Llombart-Cussac A, Muñoz M, Vidal M, Adamo B, Wolff AC, DeMichele A, Villagrasa P, Parker JS, Perou CM, Fernandez-Martinez A, Carey LA, Mittendorf EA, Martín M, Prat A, and Tolaney SM
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- Humans, Female, Receptor, ErbB-2 genetics, Treatment Outcome, Trastuzumab, Taxoids, Neoadjuvant Therapy adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Background: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status., Materials and Methods: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status., Results: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk., Conclusions: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2023
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5. Adjuvant Olaparib for Germline BRCA Carriers With HER2-Negative Early Breast Cancer: Evidence and Controversies.
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Morganti S, Bychkovsky BL, Poorvu PD, Garrido-Castro AC, Weiss A, Block CC, Partridge AH, Curigliano G, Tung NM, Lin NU, Garber JE, Tolaney SM, and Lynce F
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- Humans, Female, BRCA1 Protein genetics, BRCA2 Protein genetics, Germ-Line Mutation, Phthalazines therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
In the OlympiA study, 1 year of adjuvant olaparib significantly extended invasive disease-free survival and overall survival. The benefit was consistent across subgroups, and this regimen is now recommended after chemotherapy for germline BRCA1/2 mutation (gBRCA1/2m) carriers with high-risk, HER2-negative early breast cancer. However, the integration of olaparib in the landscape of agents currently available in the post(neo)adjuvant setting-ie, pembrolizumab, abemaciclib, and capecitabine-is challenging, as there are no data suggesting how to select, sequence, and/or combine these therapeutic approaches. Furthermore, it is unclear how to best identify additional patients who could benefit from adjuvant olaparib beyond the original OlympiA criteria. Since it is unlikely that new clinical trials will answer these questions, recommendations for clinical practice can be made through indirect evidence. In this article, we review available data that could help guide treatment decisions for gBRCA1/2m carriers with high-risk, early-stage breast cancer., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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6. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers.
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Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lønning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, and Wulf GM
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- Humans, Female, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Phosphatidylinositol 3-Kinases genetics, Prospective Studies, BRCA1 Protein genetics, Mutation, Homologous Recombination, BRCA2 Protein genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics
- Abstract
Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing., Experimental Design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973)., Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score., Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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7. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer.
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Waks AG, Desai NV, Li T, Poorvu PD, Partridge AH, Sinclair N, Spring LM, Faggen M, Constantine M, Metzger O, Alberti J, Deane J, Rosenberg SM, Frank E, Tolaney SM, Krop IE, Tung NM, Tayob N, King TA, Mittendorf EA, and Winer EP
- Abstract
De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab [HP], without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3-100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach.Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180 ., (© 2022. The Author(s).)
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- 2022
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8. Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.
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O'Sullivan CC, Ballman KV, McCall L, Kommalapati A, Zemla T, Weiss A, Mitchell M, Blinder V, Tung NM, Irvin WJ, Lee M, Goetz MP, Symmans WF, Borges VF, Krop I, Carey LA, and Partridge AH
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- Ado-Trastuzumab Emtansine adverse effects, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms prevention & control, Brain Neoplasms secondary, Breast pathology, Breast surgery, Breast Neoplasms mortality, Breast Neoplasms pathology, Chemoradiotherapy, Adjuvant adverse effects, Chemoradiotherapy, Adjuvant methods, Chemotherapy, Adjuvant adverse effects, Chemotherapy, Adjuvant methods, Clinical Trials, Phase III as Topic, Disease-Free Survival, Double-Blind Method, Female, Follow-Up Studies, Humans, Mastectomy, Middle Aged, Multicenter Studies as Topic, Neoadjuvant Therapy methods, Neoplasm Recurrence, Local prevention & control, Neoplasm, Residual, Oxazoles adverse effects, Placebos administration & dosage, Placebos adverse effects, Prospective Studies, Pyridines adverse effects, Quinazolines adverse effects, Randomized Controlled Trials as Topic, Receptor, ErbB-2 analysis, Receptor, ErbB-2 metabolism, Ado-Trastuzumab Emtansine administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Brain Neoplasms epidemiology, Breast Neoplasms therapy, Neoplasm Recurrence, Local epidemiology, Oxazoles administration & dosage, Pyridines administration & dosage, Quinazolines administration & dosage
- Abstract
This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.
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- 2021
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9. Noncontrast CMR for Detecting Early Myocardial Tissue Injury in a Swine Model of Anthracycline-Induced Cardiotoxicity.
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Nakamori S, Jang J, Tschabrunn CM, Pierce P, Goddu B, Rodriguez J, Ngo LH, Tung NM, Manning WJ, and Nezafat R
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- Animals, Cardiotoxicity, Disease Models, Animal, Early Diagnosis, Female, Heart Diseases chemically induced, Heart Diseases pathology, Heart Diseases physiopathology, Myocardial Contraction, Predictive Value of Tests, Stroke Volume, Sus scrofa, Time Factors, Ventricular Function, Left, Doxorubicin, Heart Diseases diagnostic imaging, Magnetic Resonance Imaging, Myocardium pathology
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- 2019
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10. Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis.
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Batalini F, Peacock EG, Stobie L, Robertson A, Garber J, Weitzel JN, and Tung NM
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- Diagnosis, Differential, Gene Frequency, Genes, p53 genetics, Genetic Testing, Hematopoiesis, Humans, Mosaicism, Mutation, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Li-Fraumeni Syndrome diagnosis, Li-Fraumeni Syndrome genetics
- Abstract
The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25-35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.
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- 2019
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11. International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
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Metcalfe K, Eisen A, Senter L, Armel S, Bordeleau L, Meschino WS, Pal T, Lynch HT, Tung NM, Kwong A, Ainsworth P, Karlan B, Moller P, Eng C, Weitzel JN, Sun P, Lubinski J, and Narod SA
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms diagnostic imaging, Breast Neoplasms genetics, Female, Humans, Magnetic Resonance Imaging, Mammography, Mastectomy, Middle Aged, Salpingo-oophorectomy, Breast Neoplasms prevention & control, Genes, BRCA1, Genes, BRCA2, Mutation, Risk Reduction Behavior
- Abstract
Background: Women with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017)., Methods: Eligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered., Results: Six-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27-96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and 64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country., Conclusion: For women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.
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- 2019
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12. BRCA1/2 testing: therapeutic implications for breast cancer management.
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Tung NM and Garber JE
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- Breast Neoplasms genetics, Breast Neoplasms pathology, DNA Repair genetics, Female, Germ-Line Mutation genetics, Humans, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Phthalazines adverse effects, Phthalazines therapeutic use, Piperazines adverse effects, Piperazines therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Poly(ADP-ribose) Polymerases genetics, Progression-Free Survival, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms drug therapy, Ovarian Neoplasms drug therapy
- Abstract
Testing for germline BRCA1/2 mutations has an established predictive role in breast cancer risk assessment. More recently, studies have also identified BRCA1/2 status as clinically relevant in the selection of therapy for patients already diagnosed with breast cancer. Emerging breast and ovarian cancer research indicate that BRCA status predicts responsiveness to platinum-based chemotherapy, as well as to inhibitors of poly(ADP-ribose) polymerase (PARP), owing to the ability of these interventions to inhibit DNA repair pathways. BRCA1/2 mutation testing thus has important and expanding roles in treatment planning for subsets of patients with breast cancer. Recent studies have demonstrated different activity of platinum salts in BRCA-mutated compared with non-BRCA-mutated breast cancer. Furthermore, phase II/III studies of single-agent PARP inhibitors (PARPi) have shown encouraging progression-free survival results in patients with BRCA1/2-mutated breast cancer, which led to the recent approval of olaparib, the first PARPi to be approved in breast cancer. Determining BRCA1/2 mutation status in this breast cancer subgroup could potentially expand treatment options beyond the current standard of taxane and anthracycline-based chemotherapy. Although attempts have been made to develop scoring systems that measure defects in homologous recombination repair pathways to predict response to platinum or PARPi, none have yet made it into clinical use. In this review, we summarise the recent and ongoing preclinical and clinical studies on the treatment of BRCA-associated breast cancer, and discuss efforts to identify other breast cancer patients who may be responsive to therapies effective in BRCA mutation carriers, including platinum-containing chemotherapy and PARPi.
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- 2018
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13. How to manage patients with moderate-risk germline mutations.
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Tung NM
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- Biomarkers, Tumor, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Clinical Decision-Making, Disease Management, Female, Genetic Association Studies, Genetic Counseling, Genetic Testing, Genotype, Humans, Polymorphism, Single Nucleotide, Research, Risk Assessment, Standard of Care, Breast Neoplasms genetics, Breast Neoplasms therapy, Genetic Predisposition to Disease, Germ-Line Mutation
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- 2018
14. Refining Risk Assessment in Women With Benign Breast Disease: An Ongoing Dilemma.
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Schnitt SJ, Morrow M, and Tung NM
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- Breast Neoplasms, Female, Humans, Risk Assessment, Risk Factors, Breast, Fibrocystic Breast Disease
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- 2017
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15. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
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Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, Szallasi Z, Barry WT, Winer EP, Tung NM, Isakoff SJ, Ryan PD, Greene-Colozzi A, Gutin A, Sangale Z, Iliev D, Neff C, Abkevich V, Jones JT, Lanchbury JS, Hartman AR, Garber JE, Ford JM, Silver DP, and Richardson AL
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- Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Female, Genes, BRCA1, Genes, BRCA2, Humans, Mutation, Neoplasm Staging, Odds Ratio, Platinum administration & dosage, Prognosis, Treatment Outcome, Triple Negative Breast Neoplasms mortality, Triple Negative Breast Neoplasms pathology, Allelic Imbalance, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Homologous Recombination, Loss of Heterozygosity, Telomere, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics
- Abstract
Purpose: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST)., Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy., Results: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials., Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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16. The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study.
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Iqbal J, Nussenzweig A, Lubinski J, Byrski T, Eisen A, Bordeleau L, Tung NM, Manoukian S, Phelan CM, Sun P, and Narod SA
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- Adult, Aged, Breast Neoplasms drug therapy, Female, Genetic Predisposition to Disease, Humans, Incidence, Middle Aged, Prospective Studies, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms complications, Leukemia epidemiology, Leukemia genetics, Mutation
- Abstract
Background: Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers., Methods: We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer., Results: We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3-18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11-2.19, P=0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61-6.58, P=0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR=4.76, 95% CI:1.21-12.96, P=0.03), in particular for women who received chemotherapy (SIR=8.11, 2.06-22.07, P=0.007)., Conclusions: We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer.
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- 2016
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17. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors.
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Balmaña J, Tung NM, Isakoff SJ, Graña B, Ryan PD, Saura C, Lowe ES, Frewer P, Winer E, Baselga J, and Garber JE
- Subjects
- Adult, Aged, Breast Neoplasms pathology, Cisplatin adverse effects, Disease Progression, Female, Humans, Male, Middle Aged, Neoplasms pathology, Ovarian Neoplasms pathology, Phthalazines adverse effects, Piperazines adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Cisplatin administration & dosage, Neoplasms drug therapy, Ovarian Neoplasms drug therapy, Phthalazines administration & dosage, Piperazines administration & dosage
- Abstract
Background: To establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors., Patients and Methods: Patients aged ≥ 18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50-200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1-5 or 1-10) in combination with cisplatin (60-75 mg/m(2) intravenously) on day 1 of each cycle., Results: Dose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m(2) with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m(2) with olaparib 100 mg bid days 1-10 or 50 mg bid days 1-5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m(2), respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥ 3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively., Conclusions: Olaparib in combination with cisplatin 75 mg/m(2) was not considered tolerable; intermittent olaparib (50 mg bid, days 1-5) with cisplatin 60 mg/m(2) improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2014
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18. Contemporary multidisciplinary treatment of pregnancy-associated breast cancer.
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Meisel JL, Economy KE, Calvillo KZ, Schapira L, Tung NM, Gelber S, Kereakoglow S, Partridge AH, and Mayer EL
- Abstract
Breast cancer diagnosed during pregnancy poses unique challenges. Application of standard treatment algorithms is limited by lack of level I evidence from randomized trials. This study describes contemporary multidisciplinary treatment of pregnancy-associated breast cancer (PABC) in an academic setting and explores early maternal and fetal outcomes. A search of the Dana-Farber/Harvard Cancer Center clinical databases was performed to identify PABC cases. Sociodemographic, disease, pregnancy, and treatment information, as well as data on short-term maternal and fetal outcomes, were collected through retrospective chart review. 74 patients were identified, the majority with early-stage breast cancer. Most (73.5%) underwent surgical resection during pregnancy, including 40% with sentinel lymph node biopsy and 32% with immediate reconstruction. A total of 36 patients received anthracycline-based chemotherapy during pregnancy; of those, almost 20% were on a dose-dense schedule and 8.3% also received paclitaxel. 68 patients delivered liveborn infants; over half were delivered preterm (< 37 weeks), most scheduled to allow further maternal cancer therapy. For the infants with available data, all had normal Apgar scores and over 90% had birth weight >10(th) percentile. The rate of fetal malformations (4.4%) was not different than expected population rate. Within a multidisciplinary academic setting, PABC treatment followed contemporary algorithms without apparent increase in maternal or fetal adverse outcomes. A considerable number of preterm deliveries were observed, the majority planned to facilitate cancer therapy. Continued attention to maternal and fetal outcomes after PABC is required to determine the benefit of this delivery strategy.
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- 2013
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19. Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice.
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Burga LN, Hu H, Juvekar A, Tung NM, Troyan SL, Hofstatter EW, and Wulf GM
- Subjects
- Aldehyde Dehydrogenase 1 Family, Animals, Breast cytology, Cell Line, Tumor, Cell Transformation, Neoplastic, Cells, Cultured, Epidermal Growth Factor metabolism, ErbB Receptors antagonists & inhibitors, Erlotinib Hydrochloride, Female, Genes, p53, Humans, Isoenzymes metabolism, Mammary Glands, Animal metabolism, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental metabolism, Mammary Tumor Virus, Mouse, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology, RNA Interference, Receptors, Estrogen metabolism, Retinal Dehydrogenase metabolism, BRCA1 Protein metabolism, Breast metabolism, Epithelial Cells metabolism, ErbB Receptors metabolism, Genes, BRCA1, Mammary Neoplasms, Experimental prevention & control
- Abstract
Introduction: Women who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC., Methods: Cultures of MECs were used to examine EGFR protein levels and promoter activity in response to BRCA1 suppression with inhibitory RNA. EGFR was assessed by immunoblot and immunofluorescence analysis, real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR) and flow cytometry. Binding of epidermal growth factor (EGF) to subpopulations of MECs was examined by Scatchard analysis. The responsiveness of MECs to the EGFR inhibitor erlotinib was assessed in vitro in three-dimensional cultures and in vivo. Mouse mammary tumor virus-Cre recombinase (MMTV-Cre) BRCA1flox/flox p53⁺/⁻ mice were treated daily with erlotinib or vehicle control, and breast cancer-free survival was analyzed using the Kaplan-Meier method., Results: Inhibition of BRCA1 in MECs led to upregulation of EGFR with an inverse correlation of BRCA1 with cellular EGFR protein levels (r² = 0.87) and to an increase in cell surface-expressed EGFR. EGFR upregulation in response to BRCA1 suppression was mediated by transcriptional and posttranslational mechanisms. Aldehyde dehydrogenase 1 (ALDH1)-positive MECs expressed higher levels of EGFR than ALDH1-negative MECs and were expanded two- to threefold in the BRCA1-inhibited MEC population. All MECs were exquisitely sensitive to EGFR inhibition with erlotinib in vitro. EGFR inhibition in MMTV-Cre BRCA1flox/flox p53⁺/⁻ female mice starting at age 3 months increased disease-free survival from 256 days in the controls to 365 days in the erlotinib-treated cohort., Conclusions: We propose that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction. Increased EGFR expression may confer a growth advantage to MECs with loss of BRCA1 at the earliest stages of transformation. Employing EGFR inhibition with erlotinib specifically at this premalignant stage was effective in decreasing the incidence of ER-negative breast tumors in this mouse model.
- Published
- 2011
- Full Text
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20. Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers.
- Author
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Burga LN, Tung NM, Troyan SL, Bostina M, Konstantinopoulos PA, Fountzilas H, Spentzos D, Miron A, Yassin YA, Lee BT, and Wulf GM
- Subjects
- Adult, Aged, Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase 1 Family, Breast Neoplasms enzymology, Breast Neoplasms epidemiology, Breast Neoplasms pathology, ErbB Receptors genetics, Female, Genetic Carrier Screening, Humans, Immunohistochemistry, Isoenzymes genetics, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Neoplasm genetics, RNA, Neoplasm isolation & purification, Reference Values, Retinal Dehydrogenase, Risk Factors, Tumor Cells, Cultured, BRCA1 Protein genetics, Breast Neoplasms genetics, Cell Differentiation genetics, Cell Division genetics, Mutation
- Abstract
Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1-positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n = 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERalpha; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploinsufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers.
- Published
- 2009
- Full Text
- View/download PDF
21. Malaria epidemiology in a rural area of the Mekong Delta: a prospective community-based study.
- Author
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Erhart A, Thang ND, Bien TH, Tung NM, Hung NQ, Hung LX, Tuy TQ, Speybroeck N, Cong LD, Coosemans M, and D'Alessandro U
- Subjects
- Adolescent, Adult, Aged, Antimalarials administration & dosage, Child, Child, Preschool, Epidemiologic Methods, Female, Humans, Incidence, Infant, Infant, Newborn, Malaria diagnosis, Malaria drug therapy, Malaria transmission, Male, Middle Aged, Patient Acceptance of Health Care statistics & numerical data, Vietnam epidemiology, Malaria epidemiology, Rural Health statistics & numerical data
- Abstract
Over the past 10 years, the Mekong Delta region in Vietnam has experienced fast socio-economic development with subsequent changes in malaria vectors ecology. We conducted a 2-year prospective community-based study in a coastal rural area in the southern Mekong Delta to re-assess the malaria epidemiological situation and the dynamics of transmission. The incidence rate of clinical malaria, established on 558 individuals followed for 23 months by active case detection and biannual cross-sectional surveys, was 2.6/100 person-years. Over the 2-year study period, the parasite rate and malaria seroprevalence (Plasmodium falciparum and P. vivax) decreased significantly from 2.4% to almost 0%. Passive case detection (PCD) of clinical cases and serological follow-up of newborns carried out in a larger population confirmed the low and decreasing trend of malaria transmission. The majority of fever cases were seen in the private sector and most were unnecessarily treated with antimalarials. Training and involvement of the private sector in detection of malaria cases would greatly improve the quality of health care and health information system.
- Published
- 2004
- Full Text
- View/download PDF
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