bluuebunny/crossref_metadata_2025 huggingface dataset:
Reaching the summit of discharge summaries: a quality improvement project
Authors: Richmond Richard Thomas , McFadzean Isobel Joy , Vallabhaneni Pramodh
Published: February 2021

Background

Discharge summaries need to be completed in a timely manner, to improve communication between primary and secondary care, and evidence suggests that delays in discharge summary completion can lead to patient harm.

Following a hospital health and safety review due to the sheer backlog of notes in the doctor’s room and wards, urgent action had to be undertaken to improve the discharge summary completion process at our hospital’s paediatric assessment unit. It was felt that the process would best be carried out within a quality improvement (QI) project.

Methods

Kotter’s ‘eight-step model for change’ was implemented in this QI project with the aim to clear the existing backlog of pending discharge summaries and improve the timeliness of discharge summary completion from the hospital’s paediatric assessment unit. A minimum target of 10% improvement in the completion rate of discharge summaries was set as the primary goal of the project.

Results

Following the implementation of the QI processes, we were able to clear the backlog of discharge summaries within 9 months. We improved completion within 24 hours, from <10% to 84%, within 2 months. The success of our project lies in the sustainability of the change process; to date we have consistently achieved the target completion rates since the inception of the project. As a result of the project, we were able to modify the junior doctor rota to remove discharge summary duty slots and bolster workforce on the shop floor. This is still evident in November 2020, with consistently improved discharge summary rates.

Conclusion

QI projects when conducted successfully can be used to improve patient care, as well as reduce administrative burden on junior doctors. Our QI project is an example of how Kotter’s eight-step model for change can be applied to clinical practice.
αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib
Authors: Fang Juemin , Ding Na , Guo Xianling , Sun Yan , Zhang Zhiwei , Xie Bailu , Li Zhong , Wang Hui , Mao Wei , Lin Zhicai , Qin Fei , Yuan Min , Chu Wenqi , Qin Huanlong , Qian Qijun , Xu Qing
Published: February 2021

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in China. In particular, advanced/refractory ovarian cancer lacks effective targeted therapies due to the immunosuppressive and proangiogenic tumor microenvironment. Mesothelin (MSLN) has been found to be highly expressive in most EOC. Targeting MSLN by antibodies or chimeric antigen receptor-modified T (CAR-T) cells and immune checkpoint blockades as well as apatinib, an anti-angiogenic drug, have been used in patients with refractory ovarian cancer. Apatinib was reported to promote the infiltration of CD8+T cells in lung cancer. However, the combination therapy of CAR-T secreting anti-PD-1 antibody with apatinib in EOC has not been reported.

Case presentation

Here we report a case of refractory EOC in a patient who had relapsed after multiline chemotherapy. The patient received autologous T cells that contained sequences encoding single-chain variable fragments specific for MSLN and full-length antibody for PD-1 (αPD-1). The modified T cells were called αPD-1-mesoCAR-T cells. After infusion, the copy number and PD-1 antibody secretion of the CAR-T cells were increased in the blood. By application of multimodality tumor tracking, MRI of the liver showed shrinkage of metastatic nodules from average diameter of 71.3–39.1 mm at month 2. The patient achieved partial response and survived more than 17 months. IL-6 levels in the patient fluctuated from the baseline to 2–4-folds after treatment, but side effects were mild with only grade 1 hypertension and fatigue.

Conclusion

αPD-1-mesoCAR-T cell therapy combined with apatinib demonstrates a potential therapeutic effect on advanced refractory ovarian cancer.

Trial registration number

NCT03615313.
'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies
Authors: Sinha Debottam , Srihari Sriganesh , Beckett Kirrliee , Le Texier Laetitia , Solomon Matthew , Panikkar Archana , Ambalathingal George R , Lekieffre Lea , Crooks Pauline , Rehan Sweera , Neller Michelle A. , Smith Corey , Khanna Rajiv
Published: February 2021

Background

Epstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic ‘off-the-shelf’ virus-specific T-cell therapies for post-transplant viral complications.

Methods

Taking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.

Results

These allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a ‘restriction-switching’ approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.

Conclusion

These findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.
Therapeutic depletion of CCR8+tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy
Authors: Van Damme Helena , Dombrecht Bruno , Kiss Máté , Roose Heleen , Allen Elizabeth , Van Overmeire Eva , Kancheva Daliya , Martens Liesbet , Murgaski Aleksandar , Bardet Pauline Madeleine Rachel , Blancke Gillian , Jans Maude , Bolli Evangelia , Martins Maria Solange , Elkrim Yvon , Dooley James , Boon Louis , Schwarze Julia Katharina , Tacke Frank , Movahedi Kiavash , Vandamme Niels , Neyns Bart , Ocak Sebahat , Scheyltjens Isabelle , Vereecke Lars , Nana Frank Aboubakar , Merchiers Pascal , Laoui Damya , Van Ginderachter Jo Agnes
Published: February 2021

Background

Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker.

Methods

We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models.

Results

We were able to discern two ti-Treg populations, one of which is characterized by the unique expression ofCcr8in conjunction with Treg activation markers.Ccr8is also expressed by dysfunctional CD4+and CD8+T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs.

Conclusions

Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology
Authors: Özdemir Berna C
Published: February 2021

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.
Value of systematic genetic screening of patients with amyotrophic lateral sclerosis
Authors: Shepheard Stephanie R , Parker Matthew D , Cooper-Knock Johnathan , Verber Nick S , Tuddenham Lee , Heath Paul , Beauchamp Nick , Place Elsie , Sollars Elizabeth S A , Turner Martin R , Malaspina Andrea , Fratta Pietro , Hewamadduma Channa , Jenkins Thomas M , McDermott Christopher J , Wang Dennis , Kirby Janine , Shaw Pamela J
Published: February 2021

Objective

The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.

Methods

We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.

Results

21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).

Conclusions

Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
Solid Electrolyte Interphase Stabilization Path to Lithium Metal Plating-Free High-Energy Lithium-Ion Battery Under Subzero-Temperature
Authors: Thi Tran Yen Hai , Han Jisoo , Song Seung-Wan
Published: February 2021

Lithium-ion batteries (LIBs) are ubiquitous power sources and demand for higher energy and higher performance LIBs than state-of-the-art ones continues to increase for longer range use of electric mobility and energy-storage systems. Performance of conventional LIBs is often limited or failed in tough working environments, particularly, subzero-temperatures because of reduced ionic conductivity of electrolyte and diffusion kinetics of both anode and cathode, causing lithium metal plating and dendrite growth and finally safety issue and death of LIBs. Herein, for the first time we report a lithium metal plating-free and unprecedented high-performance graphite∥LiNi0.8Co0.1Mn0.1O2 (NCM811) full-cell under subzero-temperature of −10 °C and high-voltage of 4.45 V through the construction of robust solid electrolyte interphase (SEI) layers at both anode and cathode and their structural stabilization in 1 M LiPF6 and nonflammable electrolyte. Subzero-temperature operation of commercial electrolyte-based full-cell however results in a drastic performance failure in early cycles and shows distinguishing marks such as lithium metal plating at graphite anode and irreversible phase transformation of NCM811 to disordered H3 phase with a large volume contraction. The strong correlation between anode-electrolyte and cathode-electrolyte interfacial stabilization, bulk structural stabilization of both anode and cathode, and highly reversible cycling performance under subzero-temperature is clearly demonstrated.
Solid-State Dendrite Suppressing Glass-Ceramic Electrolyte for Enabling Lithium Metal Anode
Authors: Grant Adrian , Allie Lazbourne , Lyman Devon , Nwabufoh Kenechukwu , Maxie Eleston , Smalley Yardlyne , Johnson David , Johnson Lonnie
Published: February 2021

Lithium metal anodes have long been sought to be incorporated into lithium-ion batteries (LiB) in order to increase the energy density and consequently lower the cost of LiB technology. However, Lithium metal is highly reactive and unstable with many known electrolytes. For those electrolytes stable with Lithium, there is also a risk of Lithium dendrite formation during cycling which will lead to an eventual short and catastrophic failure of the battery. In this work, we’ve developed a patented proprietary ternary glass-ceramic system, Li2CO3−Li3BO3−Li2SO4(Patent number: US10566611B2), via molten synthesis that is stable with Lithium. This can suppress dendrite growth during cycling. The bulk crystalline system exhibits lower conductivity of 2 × 10−6s cm−1at room temperature. Using rapid quenching of the system to achieve a semi-crystalline or glass phase improves the conductivity to a modest 2 × 10−5s cm−1at room temperature. This method allows ultra-thin deposition of the solid electrolyte to reduce its area specific resistance (ASR) contribution to below 30 Ω·cm2. Lithium symmetric half-cell cycling of a glass sheet shows stable, dendrite free cycling for at least 350 cycles. These characteristics make this material ideal to use as a solid-state electrolyte (SSE) separator in full cell testing.
Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes
Authors: Lee Hyun Soon , Suh Ji Yeon , Kang Byeong-Choel , Lee Eugene
Published: February 2021

In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.
Adaptive Extraction Method Based on Time-Frequency Images for Fault Diagnosis in Rolling Bearings of Motor
Authors: Ma Yunchao , Wang Chengdong , Yang Dongchen , Wang Cheng
Published: February 2021

In order to diagnose the faults of rolling bearings in motors via time-frequency analysis of bearing vibration signals quickly, this paper puts forward a method of extracting the main components from time-frequency images. A threshold is adaptively determined based on the gray histogram feature of the time-frequency images obtained from the vibration signals of the motor rolling bearings. Then, a mask template is generated by the threshold and a binarization processing. Based on a multiplication operation between the mask template and the original time-frequency image, the signal component with low energy in the time-frequency image is filtered out, and only the main components with high energy is remained for fault diagnosis, which is convenient for the subsequent identification of the faults for motor rolling bearings. The main components in the time-frequency images can be retained adaptively with the thresholds determined by the time-frequency images themselves.
A Fusion Transcription Factor–Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target
Authors: Boudjadi Salah , Pandey Puspa Raj , Chatterjee Bishwanath , Nguyen Thanh Hung , Sun Wenyue , Barr Frederic G.
Published: February 2021

Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1–induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1–independent recurrent tumors eventually form after a delay. We report here that upregulation of FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1–independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1–expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1–independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1–expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1–targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.

Significance:

In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.
Abstract GS1-08: The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies
Authors: Lee Joyce V , Housley Filomena , Yau Christina , Hemmati Golzar , Zhang Yibing , Samson Susan , Baas Carole , Rugo Hope , Matloubian Mehrdad , Goga Andrei
Published: February 2021

Immunotherapy has great potential to improve outcomes for breast cancer patients. Yet, deciding on how to rationally combine therapeutic agents and predict patient populations who would benefit remains challenging. Less than 20% of patients with metastatic breast cancer respond to current immunotherapy regiments, further demonstrating the need for research in this area. We postulate that oncogene activation leads to immune-related vulnerabilities which can be exploited to discover new immunotherapy combinations with improved efficacy. MYC is an oncogene that is frequently overexpressed in the majority of triple negative breast cancers (TNBCs), and is frequently found in disease recurrence, metastasis, and chemotherapy resistance. Despite the association of MYC with poor patient outcome, little is known about how MYC facilitates immune evasion in TNBC. Using TNBC patient datasets from the TCGA, we discovered that the MYC gene signature is anti-correlated with T-cell activation signatures and a subset of genes that regulate antigen processing and presentation with MHC-I. We further examined the effects of MYC using a MYC-driven mammary tumor mouse model (MTB-TOM). MYC activation leads to downregulation of MHC-I expression on tumor cells, poor CD8+ T cell infiltration and consequently poor response to anti-PD-L1 monotherapy. We demonstrate three methods to improve response to immunotherapy—by inactivation of MYC, by inducing an interferon response within the breast tumor, or by inducing MYC tumor synthetic lethality with a small molecule inhibitor of PIM kinases. Using these combination immunotherapy strategies, we observed that a majority of animals eradicated their breast tumors and demonstrated a durable anti-tumor response following subsequent tumor re-challenge. Our data suggest MYC is an indicator of whether a breast cancer patient will respond to immunotherapy. Analysis of the MYC gene signature as a predictor of patient response to pembrolizumab in combination with paclitaxel followed by AC in the neoadjuvant I-SPY 2 trial is on-going and will be presented. Our study is the first to describe oncogenic MYC downregulation of MHC-I in a TNBC model of breast cancer and to demonstrate translatable approaches to overcome MYC orchestrated immune evasion.

Citation Format: Joyce V Lee, Filomena Housley, Christina Yau, Golzar Hemmati, Yibing Zhang, Susan Samson, Carole Baas, Hope Rugo, Mehrdad Matloubian, Andrei Goga. The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-08.
Abstract OT-09-11: AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer
Authors: Campone Mario , Herold Christina , Wang Qiuyan , Pelekanou Vasiliki , Cartot-Cotton Sylvaine , Ling Bethany
Published: February 2021

Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved.

Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-11.
Abstract OT-13-01: A phase I study of preoperative ipilimumab, nivolumab, and talimogene laherparepvec for localized breast cancer
Authors: Nguyen Vina P. , Chang Helena R. , DiNome Maggie L. , Oseguera Denise K. , Wong Deborah J. , Nguyen Anthony T. , Shiao Stephen L. , Glaspy John A.
Published: February 2021

Background: Immunotherapy has emerged as a novel therapeutic strategy in many solid malignancies. In breast cancer, treatment with checkpoint inhibitors alone showed minimal response rates, likely because breast cancers are not sufficiently immunogenic to induce adequate baseline T cell activation. Talimogene laherparepvec (T-VEC) is an attenuated herpes simplex virus 1 (HSV-1) engineered to introduce the GM-CSF gene selectively into tumor cells to thereby enhance the immunogenicity of transduced tumor cells. T-VEC has been approved in the treatment of patients with advanced melanoma and injectable tumors. In a phase 1b clinical trial, T-VEC was well tolerated in combination with immunotherapy in patients with advanced melanoma. We evaluated the safety and tolerability of T-VEC, nivolumab, and ipilimumab in the preoperative treatment of early stage localized triple-negative breast cancer (TNBC) and hormone receptor (HR)-positive breast cancer.

Trial design and eligibility criteria: This is a single site open-label phase 1b window of opportunity trial of neoadjuvant T-VEC in combination with nivolumab and ipilimumab in patients with localized breast cancer. Twenty patients with localized TNBC or HR-positive breast cancer with palpable tumors will be included. T-VEC is administered intratumorally in week 1 (106 plaque-forming units/mL [pfu/ml]) and then every 3 weeks (108 plaque-forming units/mL [pfu/ml]) for a total of 3 injections. Nivolumab (240 mg) is administered intravenously in week 1 and every 2 weeks for a total of 4 infusions. Ipilimumab (1 mg/kg) is administered intravenously in week 1 and week 6 for a total of 2 infusions. Breast cancer surgery will be carried out after completion of study treatment. Neoadjuvant chemotherapy could be administered before or after study treatment.

Study objectives: The primary objective is to evaluate the safety and tolerability of T-VEC in combination with nivolumab and ipilimumab in this population. The secondary objectives are 1) to assess tumor response to T-VEC, nivolumab, and ipilimumab and 2) to descriptively analyze surgical specimens for evidence of tumor necrosis and inflammatory infiltration on histopathological examination.

Present accrual: To date, 5 patients have been enrolled. As described above, the projected sample size is 20 patients.

Clinical trials identification: NCT04185311

Citation Format: Vina P. Nguyen, Helena R. Chang, Maggie L. DiNome, Denise K. Oseguera, Deborah J. Wong, Anthony T. Nguyen, Stephen L. Shiao, John A. Glaspy. A phase I study of preoperative ipilimumab, nivolumab, and talimogene laherparepvec for localized breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-01.
Abstract OT-15-01: A phase II trial with safety run-in of neoadjuvant therapy with an aromatase inhibitor in combination with durvalumab (MEDI4736) in postmenopausal patients with hormone-receptor-positive (HR+) breast cancer
Authors: Khong Hung T , Goodridge Dawn N , Khakpour Nazanin , Lee M. Catherine , Laronga Christine , Armaghani Avan J , Soyano-Muller Aixa E , Han Hyo , Soliman Hatem , Costa Ricardo , Loftus Loretta , Hoover Susan J , Kiluk John V , Jameel Zena , Czerniecki Brian J
Published: February 2021

Background: HR+ breast cancer has a long dormancy and steady rate of recurrence over decades from initial diagnosis. It is a misconception to think that HR+ disease has good prognosis since long term PFS and OS are only a few percent better for HR+ disease compared with HR- disease over a follow up of 20 years. Neoadjuvant endocrine therapy has been shown to be equivalent to chemotherapy but less toxicity. Aromatase inhibitors have also been shown to have immunomodulatory activity. In order to improve short term and long term outcomes, we started an investigator-initiated study using anastrozole plus the anti-PD-L1 antibody durvalumab in the neoadjuvant treatment of HR+/HER2- breast cancer. Methods: This is an open label, phase II with safety run-in trial conducted at Moffitt Cancer Center. The primary objective is modified Preoperative Endocrine Prognostic Index (mPEPI) score of 0. Secondary objectives are clinical response rate, pathologic response rate, recurrence free survival. Correlative objectives include phenotypic changes in immune cells and cytokine patterns pre-, during- and post-treatment. Inclusion criteria include postmenopausal females, ECOG 0-1, HR+ with Allred score of 6 to 8, HER2-, cT2-cT4, any N, M0, appropriate lab values, agreeing to research biopsies. Exclusion criteria include multicentric disease, bilateral disease, autoimmunity or inflammatory disease, use of immunosuppressant, known HIV, Hep B/C infection, history of TB, h/o interstitial lung disease or pneumonitis, clinically significant cardiovascular disease, mean QTcF > 470 ms. Patients will receive anastrozole 1 mg PO daily for 6 months concurrently with durvalumab 1500 mg IV every 4 weeks for 6 cycles, followed by definitive surgery. Results: This is a trial in progress. However, limited preliminary results will be presented. Conclusion: The combination of anastrozole and durvalumab may lead to improved mPEPI score in the short term and improved RFS in the long term.

Citation Format: Hung T Khong, Dawn N Goodridge, Nazanin Khakpour, M. Catherine Lee, Christine Laronga, Avan J Armaghani, Aixa E Soyano-Muller, Hyo Han, Hatem Soliman, Ricardo Costa, Loretta Loftus, Susan J Hoover, John V Kiluk, Zena Jameel, Brian J Czerniecki. A phase II trial with safety run-in of neoadjuvant therapy with an aromatase inhibitor in combination with durvalumab (MEDI4736) in postmenopausal patients with hormone-receptor-positive (HR+) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-15-01.
Abstract PD10-01: Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017
Authors: Kurian Allison W , Morrow Monica , Katz Steven
Published: February 2021

Background: Genetic testing is increasingly important for breast and ovarian cancer risk reduction and treatment. However, little is known about trends and disparities in receipt of testing in the community and test results after diagnosis. Methods: We linked records of all women with breast cancer or ovarian cancer diagnosed from 2013-2017 in Georgia and California and reported to Surveillance, Epidemiology and End Results (SEER) registries to genetic testing results from four laboratories that did most clinical testing in the studied regions (Ambry Genetics, GeneDx, Invitae, Myriad Genetics). We combined test results performed by all laboratories over 2012-2019 with SEER data. We measured use of any test, median number of genes tested, rates of variants of uncertain significance (VUS) and pathogenic variants (PVs). Results: A total of 25.2% of 187,535 breast cancer patients, and 34.3% of 14,689 ovarian cancer patients, had genetic testing. Testing increased annually by 2% while the median number of genes tested increased annually by 28%. Among tested patients diagnosed with breast cancer in 2017, 5.2% had BRCA1/2 PVs while 4.9% had PVs in genes associated with a recognized cancer syndrome (APC, CDH1, MLH1, MSH2, MSH6, NF1, PMS2, PTEN, RET and TP53) or with emerging evidence for an increased risk of breast cancer and/or ovarian cancer (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). Among tested patients diagnosed with ovarian cancer in 2017, 11.0% had BRCA1/2 PVs while 2.3% had PVs in a syndromic gene (APC, MLH1, MSH2, MSH6, NF1, PMS2, and TP53) or an emerging breast/ovarian cancer gene (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). PVs in other tested genes were rare (generally <1%). VUS rates increased from patients diagnosed in 2013 (11.2% breast, 11.2% ovarian) to 2017 (26.4% breast, 26.8% ovarian) and were higher in racial/ethnic minorities (47.8% Asian, 46.0% Black, 40% Hispanic versus 24.6% non-Hispanic Whites diagnosed with ovarian cancer in 2017; p<.001). Conclusions: A substantial gap persists in testing ovarian cancer patients (34.5% versus nearly 100% recommended) while testing more genes was associated with a substantial racial/ethnic gap in VUS. Most clinically relevant PVs occurred in the 17 genes (ovarian cancer patients) to 20 genes (breast cancer patients) reported above; testing only these genes may optimize the clinically salient PV-to-VUS ratio, particularly for racial/ethnic minorities.

Citation Format: Allison W Kurian, Monica Morrow, Steven Katz. Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-01.
Abstract PD12-11: Patient-reported outcomes from the Phase III IMpassion031 trial of neoadjuvant atezolizumab + chemotherapy in early triple-negative breast cancer
Authors: Mittendorf Elizabeth , Harbeck Nadia , Zhang Hong (Amy) , Saji Shigehira , Jung Kyung Hae , Patel Sheetal , Patel Shilpen , Duc Anh Nguyen , Liste-Hermoso Mario , Chui Stephen Y , Barrios Carlos H
Published: February 2021

Background: In the IMpassion031 study (NCT03197935) of patients (N = 333) with invasive stage II or III early triple-negative breast cancer (eTNBC), neoadjuvant treatment with atezolizumab vs placebo, each combined with nab-paclitaxel followed by doxorubicin + cyclophosphamide, significantly improved pathologic complete response in the intent-to-treat population. Patient-reported outcomes (PROs) were collected to document patient perspectives on overall treatment burden and clinical benefit of atezolizumab + chemotherapy for neoadjuvant treatment of eTNBC. Methods: Patients received either atezolizumab 840 mg or placebo every 2 weeks (q2w) with nab-paclitaxel 125 mg/m2 every week for 12 weeks followed by atezolizumab 840 mg or placebo q2w with doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q2w for 4 cycles. After surgery, patients in the atezolizumab arm were unblinded and continued to receive atezolizumab 1200 mg every 3 weeks for 11 doses, while patients in the control arm did not receive any study treatment. Patients completed the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and single-item GP5 from the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline and day 1 of each cycle of neoadjuvant and adjuvant treatment, at end of treatment and during follow-up every 3 months during year 1, every 6 months during years 2-3, and then annually. Mean and mean change from baseline scores (with changes ≥ 10 considered clinically meaningful) in function (role and physical) and global health status/health-related quality of life (GHS/HRQoL) were predefined secondary endpoints. Mean and mean change from baseline scores in disease and treatment-related symptoms, as well as an assessment of overall side-effect bother, were exploratory endpoints. Expected results: The PROs will be compared between the atezolizumab and placebo arms to assess overall treatment burden and the effect of adding atezolizumab to neoadjuvant chemotherapy for the treatment of eTNBC.

Citation Format: Elizabeth Mittendorf, Nadia Harbeck, Hong (Amy) Zhang, Shigehira Saji, Kyung Hae Jung, Sheetal Patel, Shilpen Patel, Anh Nguyen Duc, Mario Liste-Hermoso, Stephen Y Chui, Carlos H Barrios. Patient-reported outcomes from the Phase III IMpassion031 trial of neoadjuvant atezolizumab + chemotherapy in early triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-11.
Abstract PD13-05: Delivery and activity of SN-38 by sacituzumab govitecan in breast cancer brain metastases
Authors: Brenner Andrew J , Pandey Renu , Chiou Jennifer , Floyd John , Surapreneni Prathiba , Kaklamani Virginia , Lathrop Kate , Crownover Richard , Tiziani Stefano
Published: February 2021

BACKGROUND: Sacituzumab Govitecan (SG, TRODELVY™) is an FDA approved antibody drug conjugate for treatment of metastatic triple negative breast cancer (TNBC). SG has payload and linker characteristics preferable for CNS delivery including a pH hydrolysable, a payload (SN-38) that is the active 1000-fold more potent than the parent compound CPT-11 and crosses the blood brain barrier. Our preliminary data showed SG activity in intracranial xenografts leading to our hypothesis that SG would achieve concentration of SN-38 within the breast cancer brain metastases (BCBM) that would be therapeutically relevant. METHODS: We undertook a single center, prospective, window of opportunity trial (NCT03995706) to examine the concentrations of SG, SN-38, and SN-38G in tumors patients undergoing craniotomy for BCBM (n=20) or recurrent glioblastoma (rGBM, n=10). A single dose of SG was administered at 10mg/kg IV the day prior to craniotomy. Tumor was collected and [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). following recovery patients resumed SG at 10mg/kg IV days 1 and 8 of 21 day cycle and were assessed for response or progression every third cycle by MRI. RESULTS: To date 21 patients have been treated, including 11 BCBM and 10 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For BCBM, total concentration of SN-38 varied from 173nM to 1160nM, with a mean concentration of 626nM. All GBM patients had residual measurable disease and 4 breast patients had measurable disease. With a median follow-up of 12 weeks from the first postoperative cycle in the first 14 patients, 2 partial responses from each group were observed (ORR of 28% and 50% at 12 weeks respectively). Updated results will be presented. CONCLUSIONS: SG achieves therapeutically relevant concentrations of SN-38 at 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation. A multi-center trial of SG for HER2 negative BCBM (SWOG S2007) will be enrolling soon.

Citation Format: Andrew J Brenner, Renu Pandey, Jennifer Chiou, John Floyd, Prathiba Surapreneni, Virginia Kaklamani, Kate Lathrop, Richard Crownover, Stefano Tiziani. Delivery and activity of SN-38 by sacituzumab govitecan in breast cancer brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-05.
Abstract PD15-04: Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse
Authors: Alberti Saverio , Trerotola Marco , Relli Valeria , Lattanzio Rossano , Ceci Martina , Boujnah Khouloud , Garbo Valeria , Moschella Antonino , Querzoli Patrizia , Pedriali Massimo , Antolini Laura , Guerra Emanuela
Published: February 2021

Hundreds of proteins/genes have been linked to the metastatic phenotype. However, consistent markers of tumour aggressiveness and metastatic potential in breast cancer patients were not identified, not even including proteomic analysis and large-scale genome sequencing.Metastasis-associated genes were predicted to include not only drivers of the metastatic phenotype, but also secondary events, together with adaptive, counterbalancing changes. Thus, to identify candidates with a required role in metastatic diffusion, we looked for genes that were concordantly dysregulated across orthogonal cancer metastasis settings. This led us to identify Trop-2 as uniquely upregulated and associated to metastasis in experimental models of breast cancer, as well as in other solid tumors. We identified functional inactivation of E-cadherin by Trop-2 as the main motor of metastatic diffusion of such metastatic systems. Trop-2 binding to E-cadherin inactivated its cell-cell adhesion function, through release from the cytoskeleton, for activation of β-catenin transcriptional activity. This led to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. We showed that this mechanism led to metastatic diffusion of xenotransplants growing in immunosuppressed mice. An E-cadherin-inactivation metastasis program was then shown to be recapitulated in breast cancer patients, as well as in other solid tumors, over 24 independent case series, encompassing 13,042 primary tumours. Aggressive triple-negative breast cancers were shown to be driven toward global relapse by Trop-2 overexpression, through E-cadherin inactivation and activation of β-catenin transcriptional activity. No disease recurrence was observed in control cases over +12 years of follow-up. These finding lead to a novel paradigm of a Trop-2-driven, E-cadherin-inactivation program as a main metastasis driver in solid tumors. This may open far-reaching perspectives in diagnostic procedures and anti-cancer therapies.

Citation Format: Saverio Alberti, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Patrizia Querzoli, Massimo Pedriali, Laura Antolini, Emanuela Guerra. Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-04.
Abstract PD15-07: Myc regulates alternative splicing through a network of RNA binding proteins in breast cancer
Authors: Urbanski Laura , Angarola Brittany , Brugiolo Mattia , Yurieva Marina , Park Sunghee , Anczukow Olga
Published: February 2021

The oncogenic transcription factor MYC is one of the most frequently altered genes in cancer and is highly dysregulated in aggressive tumor types, including triple negative breast cancer (TNBC). Although direct targeting of MYC or its regulators in human tumors has proved difficult, the undisputed clinical relevance of this transcription factor warrants continued study for therapeutic targeting of MYC-driven processes in tumors. Recently, we and others have shown the tumorigenic capacity of MYC is critically dependent on the RNA splicing machinery and on several splicing factor RNA-binding proteins (RBPs). Dysregulation of alternative mRNA splicing, a key step in gene expression regulation, is a hallmark of cancer, and can lead to the expression of isoforms driving tumor initiation, progression or drug resistance. Understanding which component(s) of the RNA machinery are regulated by MYC, and the functions of MYC-induced spliced isoforms, may reveal new targets that circumvent prior failures of directly targeting MYC.

Here, we examine MYC-induced changes in gene expression and alternative splicing through RNA-sequencing of breast cell lines and tumors. Using a mammary epithelial cell line with an inducible MYC system, we identified over 4,000 MYC-induced alternative splicing events as well as 378 MYC-induced RBPs. Co-expression network analysis of these RBPs in TCGA breast tumor RNA-seq data uncovered 8 RBP modules, four of which are highly correlated with MYC activity and highly expressed in TNBC. One of these modules is preserved across almost all other TCGA tumor types and remains highly correlated with MYC activity, suggesting a pan-cancer role of this co-expression module. We are now defining the functional role of these RBP modules in MYC-driven tumorigenesis in breast cancer models, as well as identifying their downstream oncogenic splicing targets. Our research project will define the role and regulation of alternative splicing in breast cancer, and more specifically in aggressive tumor types such as TNBC. Our findings will provide mechanistic insight into the role of MYC-driven splicing in tumor maintenance and will uncover novel therapeutic targets for MYC-active tumors.

Citation Format: Laura Urbanski, Brittany Angarola, Mattia Brugiolo, Marina Yurieva, Sunghee Park, Olga Anczukow. Myc regulates alternative splicing through a network of RNA binding proteins in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-07.