233 results on '"Powell SN"'
Search Results
2. Abstract MS2-2: MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways
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Powell, SN, primary
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- 2017
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3. Abstract S4-03: A functional assay for homologous recombination (HR) DNA repair and whole exome sequencing reveal that HR-defective sporadic breast cancers are enriched for genetic alterations in DNA repair genes
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Powell, SN, primary, Riaz, N, additional, Mutter, RW, additional, Ng, CKY, additional, Delsite, R, additional, Piscuoglio, S, additional, King, TA, additional, Martelotto, L, additional, Sakr, R, additional, Brogi, E, additional, Edelweiss, M, additional, Lim, R, additional, Higginson, D, additional, Weigelt, B, additional, Lee, W, additional, and Reis-Filho, JS, additional
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- 2016
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4. RAD52 (RAD52 homolog (S. cerevisiae))
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Lok, BH, primary and Powell, SN, additional
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- 2014
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5. Abstract P3-04-07: Functional BRCA-pathway defects in sporadic breast cancers rarely show a significant reduction in BRCA-pathway proteins
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Powell, SN, primary, Mutter, RW, additional, Delsite, R, additional, and Reis-Filho, JS, additional
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- 2013
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6. PD10-02: Sporadic Breast Cancers Show Defects in the BRCA1-BRCA2 Pathway of Homologous Recombination in All Biomarker-Defined Sub-Types of Breast Cancer.
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Powell, SN, primary, Mutter, RW, additional, Delsite, R, additional, Bindra, R, additional, King, T, additional, Giri, D, additional, and Park, J, additional
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- 2011
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7. P4-02-04: Androgen Receptor (AR) Expression in a Cohort of Patients (pts) with Triple Negative Breast Cancer (TNBC).
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Gucalp, A, primary, Gupta, G, additional, Patil, S, additional, Wen, YH, additional, Akram, M, additional, Brogi, E, additional, Powell, SN, additional, Ho, AY, additional, Hudis, CA, additional, and Traina, TA, additional
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- 2011
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8. P5-14-13: Favorable Prognosis in Patients with T1a,b Node-Negative Triple Negative Breast Cancers Treated with Multimodality Therapy.
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Ho, AY, primary, Gupta, G, additional, Perez, CA, additional, King, TA, additional, Patil, SM, additional, Rogers, KH, additional, Brogi, E, additional, Morrow, M, additional, Hudis, C, additional, Traina, T, additional, McCormick, B, additional, Powell, SN, additional, and Robson, ME, additional
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- 2011
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9. A DNA repair defect in a radiation-sensitive clone of a human bladder carcinoma cell line
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Powell, SN, primary, Whitaker, SJ, additional, Edwards, SM, additional, and McMillan, TJ, additional
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- 1992
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10. Use of tamoxifen with postsurgical irradiation may improve survival in estrogen and progesterone receptor-positive male breast cancer.
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Fogh S, Hirsch AE, Langmead JP, Goldberg SI, Rosenberg CL, Taghian AG, Powell SN, and Kachnic LA
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- 2011
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11. Lung dose-volume parameters and the risk of pneumonitis for patients treated with accelerated partial-breast irradiation using three-dimensional conformal radiotherapy.
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Recht A, Ancukiewicz M, Alm El-Din MA, Lu XQ, Martin C, Berman SM, Hirsch AE, Kachnic LA, Katz A, MacDonald S, Nedea EA, Stevenson MA, Powell SN, and Taghian AG
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- 2009
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12. Recombinational DNA repair in cancer and normal cells: the challenge of functional analysis.
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Willers H, Xia F, and Powell SN
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- 2002
13. Radiation therapy with iridium interstitial implant brachytherapy after lumpectomy for T1N0 breast cancer: mammographic findings.
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Monticciolo DL, Powell SN, Taghian AG, Smith BL, and Gadd MA
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- 2001
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14. IMRT for Breast Cancer--Balancing Outcomes, Patient Selection, and Resource Utilization.
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Kachnic LA and Powell SN
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- 2011
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15. In Reply to Hannoun-Levi et al.
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Hattangadi JA, Powell SN, Mauceri T, and Taghian AG
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- 2012
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16. ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure.
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Mathieu M, Nepali PR, Russell J, Askarifirouzjaei H, Baltaci M, Powell SN, Humm J, Deasy JO, and Haimovitz-Friedman A
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- Animals, Mice, Membrane Proteins metabolism, Membrane Proteins genetics, Ceramides metabolism, Membrane Microdomains metabolism, Cell Line, Tumor, Sphingomyelin Phosphodiesterase metabolism, Sphingomyelin Phosphodiesterase genetics, Mice, Inbred C57BL, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung pathology, Carcinoma, Lewis Lung radiotherapy, Carcinoma, Lewis Lung genetics, Carcinoma, Lewis Lung metabolism, Intercellular Adhesion Molecule-1 metabolism, Intercellular Adhesion Molecule-1 genetics, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes radiation effects, CD8-Positive T-Lymphocytes metabolism, Mice, Knockout
- Abstract
Background/aims: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings., Methods: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8
+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts., Results: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice., Conclusion: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)- Published
- 2024
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17. RAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability.
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Jalan M, Sharma A, Pei X, Weinhold N, Buechelmaier ES, Zhu Y, Ahmed-Seghir S, Ratnakumar A, Di Bona M, McDermott N, Gomez-Aguilar J, Anderson KS, Ng CKY, Selenica P, Bakhoum SF, Reis-Filho JS, Riaz N, and Powell SN
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- Humans, DNA Damage, DNA Breaks, Double-Stranded, DNA metabolism, DNA genetics, DNA Repair, Mutation, Neoplasms genetics, Neoplasms metabolism, Rad52 DNA Repair and Recombination Protein metabolism, Rad52 DNA Repair and Recombination Protein genetics, Genomic Instability, DNA Replication genetics, R-Loop Structures genetics, Transcription, Genetic
- Abstract
Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, RAD52's ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability., (© 2024. The Author(s).)
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- 2024
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18. Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.
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Zhu Y, Pei X, Novaj A, Setton J, Bronder D, Derakhshan F, Selenica P, McDermott N, Orman M, Plum S, Subramanyan S, Braverman SH, McMillan B, Sinha S, Ma J, Gazzo A, Khan A, Bakhoum S, Powell SN, Reis-Filho JS, and Riaz N
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- Humans, Female, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Cell Proliferation, Cell Line, Tumor, Mutation, Synthetic Lethal Mutations, DNA Copy Number Variations, BRCA2 Protein genetics, BRCA1 Protein genetics, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Background: Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear., Methods: We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher's exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations., Results: We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation., Conclusions: This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers., (© 2024. The Author(s).)
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- 2024
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19. Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.
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Ng V, Sinha S, Novaj A, Ma J, McDermott N, Pei X, Longhini ALF, Grimsley H, Gardner R, Rosen E, Powell SN, Pareja F, Mandelker D, Khan A, Setton J, Roulston A, Morris S, Koehler M, Lee N, Reis-Filho J, and Riaz N
- Abstract
Purpose: The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase., Experimental Design: We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings., Results: Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients., Conclusions: Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments., (©2024 American Association for Cancer Research.)
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- 2024
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20. Echocardiographic Functional Outcomes Following Regional Nodal Irradiation for Breast Cancer Using Volumetric Modulated Arc Therapy.
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Yu AF, White C, Zhang Z, Liu JE, Gillespie EF, McCormick B, Khan AJ, Steingart RM, Powell SN, Cahlon O, and Braunstein LZ
- Abstract
Purpose: Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation therapy (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although it often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remain uncertain., Methods and Materials: Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled in an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6 months following RT. Echocardiographic parameters were measured by a single reader and measures were compared pre- and post-RT via the signed-rank test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test., Results: Among 19 evaluable patients (median age 38 years), 89% (n = 17) received doxorubicin and 37% (n = 7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest wall and RNI. The average mean heart dose was 456 cGy (range, 187-697 cGy) and the average max heart dose was 3001 cGy (1560-4793 cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6 months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8% (SD 4.4%) pre-RT and 62.7% (SD 3.8%) 6 months post-RT ( P = .493); mean global longitudinal strain (GLS) was -19.3% (SD 2.2%) pre-RT and -19.6% (SD 1.8%) 6 months post-RT ( P = .627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses ( P > .1 for all)., Conclusions: VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS, within this limited cohort. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-ups will be needed to validate these findings., Competing Interests: The authors have no relevant conflicts of interest to disclose., (© 2024 The Author(s).)
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- 2024
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21. Increased Synthetic Cytotoxicity of Combinatorial Chemoradiation Therapy in Homologous Recombination Deficient Tumors.
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Ma J, Shah R, Bell AC, McDermott N, Pei X, Selenica P, Haseltine J, Delsite R, Khan AJ, Lok BH, Ellis MJ, Aft RF, Setton J, Reis-Filho JS, Riaz N, and Powell SN
- Abstract
Purpose: Homologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with radiation therapy (RT), leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit., Methods and Materials: Sensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using 4 assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar score (large-scale state transitions [LST]), and clonogenic survival assays. Whole-genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple-negative breast cancer was performed and HRD was defined using HRDetect., Results: BRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2 μM cisplatin and 6 Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2 Gy and cisplatin 20 μM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients in the phase 2 trial, one achieved a pathologic complete response with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without a pathologic complete response., Conclusions: HRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests, or mutational signatures, appear to be significantly more sensitive to c-RT compared with isogenic controls or tumors without HRD mutational signatures. HRD tumors may be exquisitely sensitive to c-RT which warrants further clinical investigation to guide a precision oncology approach., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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22. Spatially Fractionated Radiotherapy in the Era of Immunotherapy.
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McMillan MT, Khan AJ, Powell SN, Humm J, Deasy JO, and Haimovitz-Friedman A
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- Humans, Dose Fractionation, Radiation, Immunotherapy methods, Neoplasms radiotherapy, Neoplasms immunology
- Abstract
Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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23. A Phase II Study Evaluating the Effect of Intensity Modulated Postmastectomy Radiation Therapy on Implant Failure Rates in Breast Cancer Patients With Immediate, 2-Stage Implant Reconstruction With an MRI Imaging Correlative Substudy.
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Khan AJ, Marine CB, Flynn J, Tyagi N, Zhang Z, Thor M, Gelblum D, Mehrara B, McCormick B, Powell SN, and Ho AY
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- Humans, Female, Middle Aged, Aged, Adult, Prosthesis Failure, Quality of Life, Radiotherapy, Adjuvant adverse effects, Mammaplasty methods, Breast Implantation, Breast Neoplasms radiotherapy, Breast Neoplasms diagnostic imaging, Breast Neoplasms surgery, Mastectomy, Magnetic Resonance Imaging, Breast Implants, Radiotherapy, Intensity-Modulated adverse effects, Radiotherapy, Intensity-Modulated methods
- Abstract
Purpose: Postmastectomy radiation therapy is a mainstay in the adjuvant treatment of node-positive breast cancer, but it poses risks for women with breast reconstruction. Multibeam intensity-modulated radiation therapy improves dose conformality and homogeneity, potentially reducing complications in breast cancer patients with implant-based reconstruction. To investigate this hypothesis, we conducted a single-arm phase 2 clinical trial of breast cancer patients who underwent mastectomy/axillary dissection and prosthesis-based reconstruction., Methods and Materials: The primary endpoint was the rate of implant failure (IF) within 24 months of permanent implant placement, which would be considered an improvement over historical controls if below 16%. IF was defined as removal leading to a flat chest wall or replacement with another reconstruction. Patients were analyzed in 2 cohorts. Cohort 1 (RT-PI) received radiation therapy to the permanent implant. Cohort 2 (RT-TE) received radiation therapy to the TE. IF rates, adverse events, and quality of life were analyzed. Follow-up/postradiation therapy assessments were compared with the baseline/preradiation therapy assessments at 3 to 10 weeks after exchange surgery. A subgroup underwent serial magnetic resonance imaging (MRI) sessions to explore the association between MRI-detected changes and capsular contracture, a known adverse effect of radiation therapy., Results: Between June 2014 and March 2017, 119 women were enrolled. Cohort 1 included 45 patients, and cohort 2 had 74 patients. Among 100 evaluable participants, 25 experienced IF during the study period. IF occurred in 8/42 (19%) and 17/58 (29%) in cohorts 1 and 2, respectively. Among the IFs, the majority were due to capsular contracture (13), infection (7), exposure (3), and other reasons (2). Morphologic shape features observed in longitudinal MRI images were associated with the development of Baker grade 3 to 4 contractures., Conclusions: The rate of IF in reconstructed breast cancer patients treated with intensity-modulated radiation therapy was similar to, but not improved over, that observed with conventional, 3-dimensional-conformal methods. MRI features show promise for predicting capsular contracture but require validation in larger studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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24. Reply to G.B. Mann et al and S. Sorscher.
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Jagsi R, Griffith KA, Harris EE, Wright JL, Recht A, Taghian AG, Lee L, Moran MS, Small W Jr, Johnstone C, Rahimi A, Freedman G, Muzaffar M, Haffty B, Horst K, Powell SN, Sharp J, Sabel M, Schott A, and El-Tamer M
- Published
- 2024
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25. The Presence of Extensive Lymphovascular Invasion is Associated With Higher Risks of Local-Regional Recurrence Compared With Usual Lymphovascular Invasion in Curatively Treated Breast Cancer Patients.
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Koleoso O, Toumbacaris N, Brogi E, Zhang Z, Braunstein LZ, Morrow M, Moo TA, El-Tamer M, Marine CB, Powell SN, and Khan AJ
- Abstract
Purpose: Several data sets have demonstrated a correlation between lymphovascular invasion (LVI) and locoregional recurrence (LRR). Whether the observation of "extensive LVI" is a further and incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by (1) absence of LVI (neg), (2) LVI focal or suspicious (FS-LVI), (3) usual (nonextensive) LVI (LVI), and (4) extensive LVI (E-LVI)., Methods and Materials: Between December 2009 and August 2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathologic details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. A matched propensity score analysis compared outcomes between patients with LVI versus E-LVI., Results: Of the 8837 patients studied, 5584 were negative, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patients with E-LVI had an adverse risk profile compared with the other groups. The 5- and 10-year LRR cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI, 7.1-13) and 13% (95% CI, 10-17), respectively, which were significantly higher than those observed in the usual LVI group (6.8% [5.7-7.9] and 10% [8.8-12], respectively). A statistically significant difference in LRR was demonstrated in univariable (HR, 1.4; 95% CI, 1.03-1.89; P = .029) and multivariable regression analysis (HR, 1.62; 95% CI, 1.15-2.27; P = .005) compared with nonextensive LVI. In an alternative approach, we performed a 2:1 propensity score matching analysis comparing patients with LVI to those with E-LVI. The hazard ratio for LRR (HR, 1.47; CI 1.02-2.14; P = .041) was suggestive of a higher risk associated with E-LVI., Conclusions: Our work suggests that patients with E-LVI are at a higher risk for LRR than those with usual LVI. For patients who are borderline candidates for regional nodal irradiation or post-mastectomy radiation therapy, the finding of E-LVI might be decisive in favor of intensified treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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26. APOBEC3 mutagenesis drives therapy resistance in breast cancer.
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Gupta A, Gazzo A, Selenica P, Safonov A, Pareja F, da Silva EM, Brown DN, Zhu Y, Patel J, Blanco-Heredia J, Stefanovska B, Carpenter MA, Pei X, Frosina D, Jungbluth AA, Ladanyi M, Curigliano G, Weigelt B, Riaz N, Powell SN, Razavi P, Harris RS, Reis-Filho JS, Marra A, and Chandarlapaty S
- Abstract
Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer
1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.- Published
- 2024
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27. Breast Cancer Presenting With Intravascular Tumor Emboli in Axillary Soft Tissue: Recurrence Risk and Radiation Therapy Outcomes.
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Sarkar RR, Lavery JA, Zhang Z, Mueller BA, Zinovoy M, Cuaron JJ, McCormick B, Khan AJ, Powell SN, Wen HY, and Braunstein LZ
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Purpose: Intravascular tumor emboli in axillary soft tissue (ITE) is a rare pathologic finding in breast cancer and is associated with higher axillary nodal disease burden. The independent prognostic and predictive value of this entity is unknown, as is the role of radiation therapy for ITE., Methods and Materials: We analyzed a prospectively maintained database of breast cancer patients treated from 1992 to 2020. Patients with ITE were matched to those without (1:2) based on propensity scores to control for potential confounding factors. Locoregional (LRR) and distant recurrence (DR) were evaluated using competing risks methods accounting for death as a competing event. Overall survival (OS) and disease-free survival (DFS) were evaluated by Cox regression models. Among patients with ITE, we also evaluated whether RT improved outcomes., Results: Among 2377 total patients, 129 had ITE, of whom 126 were propensity score matched to 252 without ITE. Median follow-up from time of surgery was 5.5 years (IQR 2.3, 9.7). There were no statistically significant differences in the 5-year incidence of LRR between groups (5.4% [95% CI, 1.6%-13%] with ITE vs 10% [95% CI, 6.7%-15%] without, P = .53) or DR (24% [95% CI, 15% 35%] with ITE vs 21% [95% CI, 16%-27%] without, P = .51). Five-year OS and DFS did not differ between groups ( P > .9 for both comparisons, patients with ITE vs without ITE). In analyzing the effect of RT among patients with ITE, receipt of RT was associated with significantly improved DFS (HR, 0.34, 95% CI, 0.12-0.93, P = .04)., Conclusions: Patients with ITE do not exhibit significantly worse LRR, DR, DFS, or OS compared with a propensity-score-matched cohort without ITE. However, among patients with ITE, those who received RT demonstrated significantly improved DFS. Larger studies with longer follow-up are needed to evaluate the prognostic and predictive implications of ITE., (© 2024 The Author(s).)
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- 2024
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28. Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.
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Lee NY, Sherman EJ, Schöder H, Wray R, Boyle JO, Singh B, Grkovski M, Paudyal R, Cunningham L, Zhang Z, Hatzoglou V, Katabi N, Diplas BH, Han J, Imber BS, Pham K, Yu Y, Zakeri K, McBride SM, Kang JJ, Tsai CJ, Chen LC, Gelblum DY, Shah JP, Ganly I, Cohen MA, Cracchiolo JR, Morris LGT, Dunn LA, Michel LS, Fetten JV, Kripani A, Pfister DG, Ho AL, Shukla-Dave A, Humm JL, Powell SN, Li BT, Reis-Filho JS, Diaz LA, Wong RJ, and Riaz N
- Subjects
- Humans, Human Papillomavirus Viruses, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Hypoxia etiology, Hypoxia drug therapy, Papillomavirus Infections complications, Papillomavirus Infections therapy, Oropharyngeal Neoplasms therapy, Oropharyngeal Neoplasms drug therapy, Carcinoma drug therapy
- Abstract
Purpose: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy., Methods: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline
18 F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin., Results: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia., Conclusion: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.- Published
- 2024
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29. Correction: Foss et al. The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation. J. Pers. Med. 2022, 12 , 692.
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Foss KS, O'Daniel JM, Berg JS, Powell SN, Cadigan RJ, Kuczynski KJ, Milko LV, Saylor KW, Roberts M, Weck K, and Henderson GE
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There was an error in the original publication [...].
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- 2024
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30. Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.
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Jagsi R, Griffith KA, Harris EE, Wright JL, Recht A, Taghian AG, Lee L, Moran MS, Small W Jr, Johnstone C, Rahimi A, Freedman G, Muzaffar M, Haffty B, Horst K, Powell SN, Sharp J, Sabel M, Schott A, and El-Tamer M
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- Female, Humans, Aged, Middle Aged, Mastectomy, Segmental adverse effects, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Radiotherapy, Adjuvant, Genomics, Breast Neoplasms genetics, Breast Neoplasms radiotherapy, Breast Neoplasms surgery
- Abstract
Purpose: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors., Methods: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS., Results: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively., Conclusion: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.
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- 2024
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31. Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study.
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Tsai CJ, Yang JT, Shaverdian N, Patel J, Shepherd AF, Eng J, Guttmann D, Yeh R, Gelblum DY, Namakydoust A, Preeshagul I, Modi S, Seidman A, Traina T, Drullinsky P, Flynn J, Zhang Z, Rimner A, Gillespie EF, Gomez DR, Lee NY, Berger M, Robson ME, Reis-Filho JS, Riaz N, Rudin CM, and Powell SN
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- Humans, Female, Positron Emission Tomography Computed Tomography, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Non-Small-Cell Lung drug therapy, Breast Neoplasms radiotherapy, Breast Neoplasms etiology, Radiosurgery, Lung Neoplasms radiotherapy, Lung Neoplasms drug therapy
- Abstract
Background: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes., Methods: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete., Findings: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts., Interpretation: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted., Funding: National Cancer Institute., Competing Interests: Declaration of interests CJT is on the advisory board of Nanobiotix and Varian Medical, and received consultation fees and honorarium support from Varian Medical. AR received grants from Varian Medical, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, and the National Cancer Institute at the National Institutes of Health. DRG is a researcher with AstraZeneca, Bristol Myers Squibb, and Merck; is on the advisory board of Grail, Olympus, Johnson & Johnson, Varian Medical, and Medtronic; and served as a speaker for MedLearning Group. NYL is on the advisory board of Merck, Merck EMD, Nanobiotix, and Galera Therapeutics; and received consulting fees from Shanghai JoAnn Medical Technology, Yingming Consulting, and Varian Medical. NR received research support from Invitae. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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32. Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial.
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Gillespie EF, Yang JC, Mathis NJ, Marine CB, White C, Zhang Z, Barker CA, Kotecha R, McIntosh A, Vaynrub M, Bartelstein MK, Mitchell A, Guttmann DM, Yerramilli D, Higginson DS, Yamada YJ, Kohutek ZA, Powell SN, Tsai J, and Yang JT
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- Male, Adult, Humans, Proportional Hazards Models, Regression Analysis, Standard of Care, Bone Neoplasms drug therapy
- Abstract
Purpose: External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE)., Methods: In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS)., Results: A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm ( P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01)., Conclusion: Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.
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- 2024
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33. Proton Reirradiation for High-Risk Recurrent or New Primary Breast Cancer.
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Chakraborty MA, Khan AJ, Cahlon O, Xu AJ, Braunstein LZ, Powell SN, and Choi JI
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Radiotherapy is an integral component of multidisciplinary breast cancer care. Given how commonly radiotherapy is used in the treatment of breast cancer, many patients with recurrences have received previous radiotherapy. Patients with new primary breast cancer may also have received previous radiotherapy to the thoracic region. Curative doses and comprehensive field photon reirradiation (reRT) have often been avoided in these patients due to concerns for severe toxicities to organs-at-risk (OARs), such as the heart, lungs, brachial plexus, and soft tissue. However, many patients may benefit from definitive-intent reRT, such as patients with high-risk disease features such as lymph node involvement and dermal/epidermal invasion. Proton therapy is a potentially advantageous treatment option for delivery of reRT due to its lack of exit dose and greater conformality that allow for enhanced non-target tissue sparing of previously irradiated tissues. In this review, we discuss the clinical applications of proton therapy for patients with breast cancer requiring reRT, the currently available literature and how it compares to historical photon reRT outcomes, treatment planning considerations, and questions in this area warranting further study. Given the dosimetric advantages of protons and the data reported to date, proton therapy is a promising option for patients who would benefit from the added locoregional disease control provided by reRT for recurrent or new primary breast cancer.
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- 2023
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34. Most large structural variants in cancer genomes can be detected without long reads.
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Choo ZN, Behr JM, Deshpande A, Hadi K, Yao X, Tian H, Takai K, Zakusilo G, Rosiene J, Da Cruz Paula A, Weigelt B, Setton J, Riaz N, Powell SN, Busam K, Shoushtari AN, Ariyan C, Reis-Filho J, de Lange T, and Imieliński M
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- Humans, Female, Sequence Analysis, DNA methods, Genome, Human genetics, Chromosome Aberrations, High-Throughput Nucleotide Sequencing methods, Genomic Structural Variation genetics, Genomics methods, Breast Neoplasms
- Abstract
Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure., (© 2023. The Author(s).)
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- 2023
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35. Activation of STING in Response to Partial-Tumor Radiation Exposure.
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Mathieu M, Budhu S, Nepali PR, Russell J, Powell SN, Humm J, Deasy JO, and Haimovitz-Friedman A
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- Animals, Mice, Female, Carcinoma, Lewis Lung radiotherapy, Ataxia Telangiectasia Mutated Proteins metabolism, Cytokines metabolism, Cell Line, Tumor, Membrane Proteins metabolism, Mice, Inbred BALB C, Nucleotidyltransferases metabolism, Mice, Inbred C57BL
- Abstract
Purpose: To determine the mechanisms involved in partial volume radiation therapy (RT)-induced tumor response., Methods and Materials: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and Lewis lung carcinoma (LLC cells; WT, Crispr/Cas9 Sting KO, and Atm KO) injected in the flank of C57Bl/6, cGAS, or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2 × 2 cm collimator on a microirradiator allowing precise irradiation. Tumors and blood were collected at 6, 24, and 48 hours post-RT and assessed for cytokine measurements., Results: There is a significant activation of the cGAS/STING pathway in the hemi-irradiated tumors compared with control and to 100% exposed 67NR tumors. In the LLC model, we determined that an ATM-mediated noncanonical activation of STING is involved. We demonstrated that the partial exposure RT-mediated immune response is dependent on ATM activation in the tumor cells and on the STING activation in the host, and cGAS is dispensable. Our results also indicate that partial volume RT stimulates a proinflammatory cytokine response compared with the anti-inflammatory profile induced by 100% tumor volume exposure., Conclusions: Partial volume RT induces an antitumor response by activating STING, which stimulates a specific cytokine signature as part of the immune response. However, the mechanism of this STING activation, via the canonical cGAS/STING pathway or a noncanonical ATM-driven pathway, depends on the tumor type. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade and other antitumor therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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36. Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.
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Setton J, Hadi K, Choo ZN, Kuchin KS, Tian H, Da Cruz Paula A, Rosiene J, Selenica P, Behr J, Yao X, Deshpande A, Sigouros M, Manohar J, Nauseef JT, Mosquera JM, Elemento O, Weigelt B, Riaz N, Reis-Filho JS, Powell SN, and Imieliński M
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- Humans, Chromosome Inversion, Translocation, Genetic genetics, Homologous Recombination, Cytogenetic Analysis, BRCA1 Protein deficiency, BRCA1 Protein genetics, BRCA2 Protein deficiency, BRCA2 Protein genetics, DNA Repair genetics, Neoplasms genetics, Chromosome Aberrations classification
- Abstract
Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations
1 . Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure2 . Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells., (© 2023. The Author(s).)- Published
- 2023
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37. A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells.
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Ahmed-Seghir S, Jalan M, Grimsley HE, Sharma A, Twayana S, Kosiyatrakul ST, Thompson C, Schildkraut CL, and Powell SN
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- Humans, Phosphorylation, Escherichia coli genetics, Genomics, Ataxia Telangiectasia Mutated Proteins genetics, DNA Damage, DNA Replication
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When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global checkpoint pathway have been identified, but the response to a single replication fork barrier (RFB) is poorly understood. We utilized the Escherichia coli -based Tus- Ter system in human MCF7 cells and showed that the Tus protein binding to TerB sequences creates an efficient site-specific RFB. The single fork RFB was sufficient to activate a local, but not global, ATR-dependent checkpoint response that leads to phosphorylation and accumulation of DNA damage sensor protein γH2AX, confined locally to within a kilobase of the site of stalling. These data support a model of local management of fork stalling, which allows global replication at sites other than the RFB to continue to progress without delay., Competing Interests: SA, MJ, HG, AS, ST, SK, CT, CS, SP No competing interests declared, (© 2023, Ahmed-Seghir, Jalan et al.)
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- 2023
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38. Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer.
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Choi JI, McCormick B, Park P, Millar M, Walker K, Tung CC, Huang S, Florio P, Chen CC, Lozano A, Hanlon AL, Fox J, Xu AJ, Zinovoy M, Mueller B, Bakst R, LaPlant Q, Braunstein LZ, Khan AJ, Powell SN, and Cahlon O
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Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT)., Methods and Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified. Comparative VMAT plans (XRT1) using matched BP dose constraints were developed. A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy. Incidence of brachial plexopathy was also assessed., Results: Ten consecutive patients were identified. Median time between RT courses was 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (range, 42.6-60.0), 50.4 Gy relative biologic effectiveness (RBE) (45.0-64.4), and 102.4 Gy (RBE) (95.0-120.0), respectively. Median follow-up was 15 months (5-33) and 18 months for living patients (11-33) Mean BP max was 37.5 Gy (RBE) for PBT1 and 36.9 Gy for XRT1. Target volume coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were numerically lower for XRT1 versus PBT1. Similarly, axilla I-III and supraclavicular area coverage were significantly higher for PBT2 than XRT2 at dose levels of V55%, V65%, V75%, V85%, and V95%. Only axilla I V55% did not reach significance ( P = .06) favoring PBS-PT. Two patients with high cumulative BPmax (95.2 Gy [RBE], 101.6 Gy [RBE]) developed brachial plexopathy symptoms with ulnar nerve distribution neuropathy without pain or weakness (1 of 2 had symptom resolution after 6 months without intervention)., Conclusions: PBS-PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high-risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality., Competing Interests: J. Isabelle Choi reports personal fees from Varian Medical Systems outside of the scope of this work., (© 2023 The Author(s).)
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- 2023
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39. Metaplastic carcinoma of the breast: matched cohort analysis of recurrence and survival.
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Narayan P, Kostrzewa CE, Zhang Z, O'Brien DAR, Mueller BA, Cuaron JJ, Xu AJ, Bernstein MB, McCormick B, Powell SN, Khan AJ, Wen HY, and Braunstein LZ
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- Humans, Female, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local pathology, Breast pathology, Cohort Studies, Prognosis, Breast Neoplasms therapy, Breast Neoplasms drug therapy, Carcinoma, Ductal, Breast pathology, Triple Negative Breast Neoplasms pathology
- Abstract
Purpose: Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer, defined as mammary carcinoma with squamous or mesenchymal differentiation, that may include spindle cell, chondroid, osseous, or rhabdomyoid differentiation patterns. The implications of MBC recurrence and survival outcomes remains unclear., Methods: Cases were ascertained from a prospectively maintained institutional database of patients treated from 1998 to 2015. Patients with MBC were matched 1:1 to non-MBC cases. Cox proportional-hazards models and Kaplan-Meier estimates were used to evaluate outcome differences between cohorts., Results: 111 patients with MBC were matched 1:1 with non-MBC patients from an initial set of 2400 patients. Median follow-up time was 8 years. Most patients with MBC received chemotherapy (88%) and radiotherapy (71%). On univariate competing risk regression, MBC was not associated with locoregional recurrence (HR = 1.08; p = 0.8), distant recurrence (HR = 1.65; p = 0.092); disease-free survival (HR = 1.52; p = 0.065), or overall survival (HR = 1.56; p = 0.1). Absolute differences were noted in 8-year disease-free survival (49.6% MBC vs 66.4% non-MBC) and overall survival (61.3% MBC vs 74.4% non-MBC), though neither of these reached statistical significance (p = 0.07 and 0.11, respectively)., Conclusion: Appropriately-treated MBC may exhibit recurrence and survival outcomes that are difficult to distinguish from those of non-MBC. While prior studies suggest that MBC has a worse natural history than non-MBC triple-negative breast cancer, prudent use of chemotherapy and radiotherapy may narrow these differences, although studies with more power will be required to inform clinical management. Longer follow-up among larger populations may further elucidate the clinical and therapeutic implications of MBC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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40. Accelerated Partial Breast Irradiation: Association of Dosimetric Parameters With Patient-Reported Outcomes.
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Lapen K, Fiasconaro M, Zhang Z, Abaya A, McCormick B, Xu AJ, Cuaron J, Powell SN, Kahn AJ, Gillespie EF, and Braunstein LZ
- Abstract
Purpose: Accelerated partial breast irradiation (APBI) after breast-conserving surgery offers a well-tolerated adjuvant radiation therapy option for patients with breast cancer. We sought to describe patient-reported acute toxicity as a function of salient dosimetric parameters during and after an APBI regimen of 40 Gy in 10 once-daily fractions., Methods and Materials: From June 2019 to July 2020, patients undergoing APBI were assigned a weekly, response-adapted, patient reported outcomes-common terminology criteria for adverse events-based acute toxicity assessment. Patients reported acute toxicity during treatment and for up to 8 weeks after treatment. Dosimetric treatment parameters were collected. Descriptive statistics and univariable analyses were used to summarize patient-reported outcomes and their correlation to corresponding dosimetric measures, respectively., Results: Overall, 55 patients who received APBI completed a total of 351 assessments. Median planning target volume was 210 cc (range, 64-580 cc), and median planning target volume:ipsilateral breast volume ratio was 0.17 (range, 0.05-0.44). Overall, 22% of patients reported moderate breast enlargement and 27% reported maximum skin toxicity as severe or very severe. Furthermore, 35% of patients reported fatigue, and 44% of patients reported pain in the radiated area as moderate to very severe. Median time to first report of any moderate to very severe symptom was 10 days (interquartile range, 6-27 days). By 8 weeks after APBI, most patients reported resolution of symptoms, with 16% reporting residual moderate symptoms. Upon univariable analysis, none of the ascertained salient dosimetric parameters were associated with maximum symptoms or with the presence of moderate to very severe toxicity., Conclusions: Weekly assessments during and after APBI showed that patients experienced moderate to very severe toxicities, most commonly skin toxicity, but that these typically resolved by 8 weeks after radiation therapy. More comprehensive evaluations among larger cohorts are warranted to define the precise dosimetric parameters that correspond to outcomes of interest., (© 2023 The Author(s).)
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- 2023
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41. Locoregional Control Benefit of a Tumor Bed Boost for Ductal Carcinoma In Situ.
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Dreyfuss AD, Max D, Flynn J, Zhang Z, Gillespie EF, Xu A, Cuaron J, Mueller B, Khan AJ, Cahlon O, Powell SN, McCormick B, and Braunstein LZ
- Abstract
Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces invasive and in situ recurrences. Whereas landmark studies suggest that a tumor bed boost improves local control for invasive breast cancer, the benefit in DCIS remains less certain. We evaluated outcomes of patients with DCIS treated with or without a boost., Methods and Materials: The study cohort comprised patients with DCIS who underwent BCS at our institution from 2004 to 2018. Clinicopathologic features, treatment parameters, and outcomes were ascertained from medical records. Patient and tumor characteristics were evaluated relative to outcomes using univariable and multivariable Cox models. Recurrence-free survival (RFS) estimates were generated using the Kaplan-Meier method., Results: We identified 1675 patients who underwent BCS for DCIS (median age, 56 years; interquartile range, 49-64 years). Boost RT was used in 1146 cases (68%) and hormone therapy in 536 (32%). At a median follow-up of 4.2 years (interquartile range, 1.4-7.0 years), we observed 61 locoregional recurrence events (56 local, 5 regional) and 21 deaths. Univariable logistic regression demonstrated that boost RT was more common among younger patients ( P < .001) with positive or close margins ( P < .001) and with larger tumors ( P < .001) of higher grade ( P = .025). The 10-year RFS rate was 88.8% among those receiving a boost and 84.3% among those without a boost ( P = .3), and neither univariable nor multivariable analyses revealed an association between boost RT and locoregional recurrence., Conclusions: Among patients with DCIS who underwent BCS, use of a tumor bed boost was not associated with locoregional recurrence or RFS. Despite a preponderance of adverse features among the boost cohort, outcomes were similar to those of patients not receiving a boost, suggesting that a boost may mitigate risk of recurrence among patients with high-risk features. Ongoing studies will elucidate the extent to which a tumor bed boost influences disease control rates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)
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- 2023
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42. Obturator Anterior Dislocation After Direct Anterior Total Hip Arthroplasty in a Patient with Ehlers-Danlos Syndrome: A Case Report.
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Powell SN, Nash JK, and Kildow BJ
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- Female, Humans, Aged, Pelvis surgery, Arthroplasty, Replacement, Hip adverse effects, Hip Dislocation diagnostic imaging, Hip Dislocation etiology, Hip Dislocation surgery, Joint Dislocations surgery, Ehlers-Danlos Syndrome complications, Ehlers-Danlos Syndrome surgery
- Abstract
Case: A 71-year-old woman with Ehlers-Danlos syndrome suffered an atraumatic obturator dislocation status post direct anterior total hip arthroplasty. A closed reduction under conscious sedation was attempted, but was unsuccessful. Repeat closed reduction under full general anesthesia with paralysis and fluoroscopic guidance was successful at reducing the femoral prosthesis out of the pelvis and back into an appropriate position., Conclusion: Atraumatic obturator dislocations after total hip arthroplasty are exceedingly rare. General anesthesia with full paralysis is helpful for a successful closed reduction, and open reduction may be necessary to remove the femoral prosthesis from the pelvis., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C70)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)
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- 2023
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43. Outcomes of Breast Cancer Patients with High Volume of Residual Disease Following Neoadjuvant Chemotherapy.
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Zhang YH, Montagna G, Flynn J, Gillespie EF, Mamtani A, Zhang Z, Braunstein LZ, Powell SN, Morrow M, Barrio A, and Khan AJ
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- Humans, Female, Neoadjuvant Therapy methods, Neoplasm, Residual, Chemotherapy, Adjuvant methods, Neoplasm Recurrence, Local pathology, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
Purpose: The use of neoadjuvant chemotherapy (NAC) in patients with operable breast cancer allows for assessment of treatment response and subsequent tailoring of adjuvant therapy. Data are limited with respect to outcomes among patients with a heavy residual tumor burden after NAC. We report outcomes in patients who had exceptionally poor responses to NAC: those with >9 involved nodes after NAC or with 5 cm or more of residual disease in the breast., Methods and Materials: Between June 2014 and April 2020, 1511 patients with breast cancer received NAC followed by surgery at our institution. Poor responders, defined as those with positive nodes or residual tumor in the breast, were identified for analysis. Patients were further classified into 3 groups for comparison purposes: (1) 1 to 3 positive nodes; (2) 4 to 9 positive nodes; or (3) >9 positive nodes and/or >5 cm of residual tumor, which was defined as high-volume residual (HVR). Recurrence and survival outcomes were compared based on residual disease burden after NAC., Results: Among 934 poor responders, 539 patients had 1 to 3 positive nodes (ypN1), 215 had 4 to 9 positive nodes (ypN2), and 180 had HVR disease. Specifically, 118 had >9 positive nodes (HVR), and 62 patients had >5 cm of residual tumor in the breast. With a median follow-up of 31 months (interquartile range, 18-46), the 5-year overall survival rate was 88% among ypN1, 76% among ypN2, and 72% among patients with HVR disease (P < .001). The 5-year distant recurrence-free survival and locoregional recurrence incidences were 82% and 7.6% among ypN1 versus 67% and 8.4% among ypN2 versus 53% and 12% among HVR, respectively., Conclusions: Our work suggests that patients with HVR disease are at high risk for locoregional and distant recurrence as well as death, despite best available standard-of-care treatment. Intensification of locoregional therapies and/or alternative adjuvant systemic treatment may improve outcomes in these poor responders., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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44. Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases.
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Wijetunga NA, Goglia AG, Weinhold N, Berger MF, Cislo M, Higginson DS, Chabot K, Osman AM, Schaff L, Pentsova E, Miller AM, Powell SN, Boire A, and Yang JT
- Subjects
- Humans, Protons, Biomarkers, Tumor, Mutation, Circulating Tumor DNA, Craniospinal Irradiation, Lung Neoplasms drug therapy, Meningeal Carcinomatosis
- Abstract
Purpose: Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response., Experimental Design: We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan-Meier analysis was used to associate genomic changes with survival., Results: The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5-21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05)., Conclusions: In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response., (©2022 American Association for Cancer Research.)
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- 2023
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45. Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis.
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Yang JT, Wijetunga NA, Pentsova E, Wolden S, Young RJ, Correa D, Zhang Z, Zheng J, Steckler A, Bucwinska W, Bernstein A, Betof Warner A, Yu H, Kris MG, Seidman AD, Wilcox JA, Malani R, Lin A, DeAngelis LM, Lee NY, Powell SN, and Boire A
- Subjects
- Humans, Protons, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Craniospinal Irradiation adverse effects, Lung Neoplasms drug therapy, Proton Therapy adverse effects, Meningeal Carcinomatosis radiotherapy, Meningeal Carcinomatosis drug therapy
- Abstract
Purpose: Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT., Patients and Methods: We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs)., Results: Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs ( P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months)., Conclusion: Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.
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- 2022
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46. The Effect of Surgeon Referral and a Radiation Oncologist Productivity-Based Metric on Radiation Therapy Receipt Among Elderly Women With Early Stage Breast Cancer: Analysis From a Tertiary Cancer Network.
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Cha EE, Patel MA, Zhang YH, Lobaugh S, Zhang Z, McCormick B, Braunstein LZ, Cahlon O, Powell SN, Morrow M, Khan A, and Gillespie EF
- Abstract
Purpose: : Guidelines for early-stage breast cancer allow for radiation therapy (RT) omission after breast conserving surgery among older women, though high utilization of RT persists. This study explored surgeon referral and the effect of a productivity-based bonus metric for radiation oncologists in an academic institution with centralized quality assurance review., Methods and Materials: : We evaluated patients ≥70 years of age treated with breast conserving surgery for estrogen receptor (ER)+ pT1N0 breast cancer at a single tertiary cancer network between 2015 and 2018. The primary outcomes were radiation oncology referral and RT receipt. Covariables included patient and physician characteristics and treatment decisions before versus after productivity metric implementation. Univariable generalized linear effects models explored associations between these outcomes and covariables., Results: : Of 703 patients included, 483 (69%) were referred to radiation oncology and 273 (39%) received RT (among those referred, 57% received RT). No difference in RT receipt pre- versus post-productivity metric implementation was observed ( P = .57). RT receipt was associated with younger patient age (70-74 years; odds ratio [OR], 2.66; 95% confidence interval [CI], 1.54-4.57) and higher grade (grade 3; OR, 7.75; 95% CI, 3.33-18.07). Initial referral was associated with younger age (70-74; OR, 5.64; 95% CI, 3.37-0.45) and higher performance status (Karnofsky performance status ≥90; OR, 5.34; 95% CI, 2.63-10.83)., Conclusions: : Nonreferral to radiation oncology accounted for half of RT omission but was based on age and Karnofsky performance status, in accordance with guidelines. Lack of radiation oncologist practice change in response to misaligned financial incentives is reassuring, potentially reflecting incentive design and/or centralized quality assurance review. Multi-institutional studies are needed to confirm these findings., (© 2022 The Authors.)
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- 2022
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47. Impact of prior anterior instability on shoulder arthroplasty outcomes: a systematic review.
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Vopat ML, Peebles AM, Hanson JA, Powell SN, Mologne MS, Jildeh TR, Foster MJ, Eble SK, Millett PJ, and Provencher CMT
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Background: Anterior shoulder instability (ASI) is a frequently encountered pathology. Patients with a history of ASI have an increased rate of developing glenohumeral osteoarthritis and becoming candidates for shoulder arthroplasty. This systematic review aims to synthesize outcomes for patients undergoing shoulder arthroplasty with a history of ASI., Methods: A comprehensive literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) using PubMed, Embase, OVID Medline, Scopus, CINAHL, Web of Science, and Cochrane databases for studies evaluating the impact of prior ASI on total shoulder arthroplasty (TSA), reverse TSA, and/or hemiarthroplasty outcomes, with a minimum follow-up of 12 months. Studies were graded by level of evidence and data concerning patient demographics and outcomes were extracted., Results: Sixteen articles met the inclusion criteria, including 596 patients (413 male, 181 female). The average age of the control and prior ASI groups were 57.5 and 57.0 years, respectively. Overall, 251 patients were treated operatively, 132 nonoperatively, and 213 were controls without a history of prior ASI. Shoulder arthroplasty techniques included TSA (436 shoulders), reverse TSA (130 shoulders), and hemiarthroplasty (14 shoulders). Prior anterior stabilization management included soft tissue repair, bony augmentation, and nonoperative treatment. Almost all studies reported no significant difference in subjective and functional arthroplasty outcomes between control and prior ASI groups, or between patients with prior ASI treated nonoperatively vs. surgically., Conclusion: Shoulder arthroplasty in the setting of prior ASI results in improved subjective and functional outcome scores that are comparable to patients without a history of instability., (© 2022 The Authors.)
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- 2022
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48. A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.
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Sittenfeld SMC, Zabor EC, Hamilton SN, Kuerer HM, El-Tamer M, Naoum GE, Truong PT, Nichol A, Smith BD, Woodward WA, Moo TA, Powell SN, Shah CS, Taghian AG, Abu-Gheida I, and Tendulkar RD
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- Female, Humans, Lymph Nodes pathology, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Radiotherapy, Adjuvant, Retrospective Studies, Breast Neoplasms pathology, Mastectomy
- Abstract
Background: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial., Methods: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM)., Results: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model., Conclusions: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2022
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49. Public Interest in Population Genetic Screening for Cancer Risk.
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Roberts MC, Foss KS, Henderson GE, Powell SN, Saylor KW, Weck KE, and Milko LV
- Abstract
An emerging role for DNA sequencing is to identify people at risk for an inherited cancer syndrome in order to prevent or ameliorate the manifestation of symptoms. Two cancer syndromes, Hereditary Breast and Ovarian Cancer and Lynch Syndrome meet the "Tier 1" evidence threshold established by the Centers for Disease Control and Prevention (CDC) for routine testing of patients with a personal or family history of cancer. Advancements in genomic medicine have accelerated public health pilot programs for these highly medically actionable conditions. In this brief report, we provide descriptive statistics from a survey of 746 US respondents from a Qualtrics panel about the public's awareness of genetic testing, interest in learning about their cancer risk, and likelihood of participating in a population genetic screening (PGS) test. Approximately of half the respondents were aware of genetic testing for inherited cancer risk (n = 377/745, 50.6%) and would choose to learn about their cancer risk (n-309/635, 48.7%). Characteristics of those interested in learning about their cancer risk differed by educational attainment, age, income, insurance status, having a primary care doctor, being aware of genetic testing, and likelihood of sharing information with family ( p < 0.05). A sizeable majority of the respondents who were interested in about learning their cancer risk also said that they were likely to participate in a PGS test that involved a clinical appointment and blood draw, but no out-of-pocket cost (n = 255/309, 82.5%). Reasons for not wanting to participate included not finding test results interesting or important, concerns about costs, and feeling afraid to know the results. Overall, our results suggest that engaging and educating the general population about the benefits of learning about an inherited cancer predisposition may be an important strategy to address recruitment barriers to PGS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roberts, Foss, Henderson, Powell, Saylor, Weck and Milko.)
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- 2022
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50. Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer.
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Moore G, Majumdar R, Powell SN, Khan AJ, Weinhold N, Yin S, and Higginson DS
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- Female, Homologous Recombination, Humans, Mutation, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, BRCA2 Protein genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta-mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures., Implications: Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency., (©2022 American Association for Cancer Research.)
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- 2022
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