bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt; 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

Abstract
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 &lt;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&lt;.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

Abstract
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

Abstract
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.