bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES12-1: Clinical indications of PARP1 inhibitors and other targets
Authors: Telli ML
Published: March 2020

Two PARP1 inhibitors, olaparib and talazoparib, garnered regulatory approvals for the treatment of advanced HER2-negative breast cancer associated with a germline BRCA1 or BRCA2 mutation in 2018. The approvals were based on a prolongation of progression-free survival with PARP inhibitor monotherapy compared to non-DNA damaging single agent chemotherapy in the 1st - 4th line metastatic setting. While the availability of these therapies has increased therapeutic options for this group of patients, median progression-free survival ranged from 7 - 8.6 months and no overall survival advantage has been observed to date. While response rates with PARP inhibitor monotherapy are high, development of resistance remains a significant clinical problem. Further, how PARP inhibitor monotherapy compares with platinum-based chemotherapy in this group of patients has been unclear. The recently reported phase III BROCADE 3 clinical trial examining carboplatin and paclitaxel with the addition of veliparib or placebo added important insights. This was the first phase III trial in patients with advanced germline BRCA1 and BRCA2 mutation-associated HER2-negative breast cancer that examined the use of a PARP inhibitor combined with DNA damaging chemotherapy in the 1st-3rd line setting followed by blinded monotherapy after discontinuation of chemotherapy. The median progression-free survival was significantly prolonged with the addition of veliparib (14.5 versus 12.6 months) with 26% of patients in the veliparib arm remaining progression-free at 36 months. Median overall survival was 33.5 months in the veliparib arm compared to 28.2 months in placebo with 44% of patients in the placebo arm crossing over to receive veliparib after disease progression. While important differences exist between these three trials, BROCADE 3 has reported the longest progression-free and overall survival to date with PARP inhibitor therapy in advanced germline BRCA1 and BRCA2 mutation-associated breast cancer. Beyond BRCA1 and BRCA2, PARP inhibitors are also being investigated in homologous recombination deficient advanced breast cancer in a number of clinical trials. In the Talazoparib Beyond BRCA study, high clinical activity was noted in germline PALB2 mutation carriers. The Olaparib Expanded trial is ongoing.

Citation Format: ML Telli. Clinical indications of PARP1 inhibitors and other targets [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-1.
Abstract ES2-1: Guiding decisions to omit radiotherapy after breast-conserving surgery for DCIS. Can genomic biomarkers help?
Authors: Rakovitch E
Published: March 2020

Most women diagnosed with ductal carcinoma in situ (DCIS) will be treated with breast-conserving surgery followed by whole breast radiation. We will review the evolving role of genomic biomarkers to personalize radiotherapy treatment recommendations after breast-conserving surgery for DCIS.

Citation Format: E Rakovitch. Guiding decisions to omit radiotherapy after breast-conserving surgery for DCIS. Can genomic biomarkers help? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES2-1.
Abstract ES3-1: Targeted approach to breast cancer surveillance in high risk women: update of the newest technologies and how to use them
Authors: Jochelson M
Published: March 2020

In multiple prospective randomized trials, screening mammography alone has been demonstrated to reduce breast cancer mortality by approximately 30%. These studies did not account for differences in breast cancer risk. With increasing knowledge of factors that increase breast cancer risk including pathologic mutations, thoracic radiation at a young age, strong family history and incidence of some high-risk lesions, it has become clear that supplemental breast imaging might be necessary to improve early breast cancer detection and outcomes in women at increased risk. Additionally, it has become clear that different high-risk categories are associated with different types and presentations of breast cancer and that these differences might also translate into different imaging strategies. This presentation will address the standard breast cancer imaging tools such as Digital Mammography and Ultrasound and compare them with the newest imaging techniques in breast cancer imaging including Digital Breast Tomosynthesis, and physiologic imaging with a relatively new technology for screening: Contrast Enhanced Digital Mammography and Contrast Enhanced Breast MRI to include the most recent data on Abbreviated Breast MRI. There will be a discussion of fine-tuning the screening strategies based on the specific risk factors which will address the ideal frequency of screening, when screening should start and end and the utility of mammography and ultrasound in women undergoing breast MRI.

Citation Format: M Jochelson. Targeted approach to breast cancer surveillance in high risk women: update of the newest technologies and how to use them [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES3-1.
Abstract ES4-3: The genomic landscape of endocrine-resistant metastatic breast cancer
Authors: Razavi P
Published: March 2020

Recent efforts to characterize the genomes of metastatic breast cancers hold promise for understanding the evolution of the disease through comparative analyses with primary breast cancers. However, these analyses have proven challenging due to the number of differences including differences in tumor representation and spatial tumor heterogeneity resulting in less accurate representation of metastatic disease, and temporal heterogeneity often due to the selective pressures of treatments, all of which may independently alter the ongoing natural evolution of the tumor containing disrupted DNA and/or DNA repair processes. Advances in genomic analyses and large repositories of samples with detailed clinical annotation have enabled rational deconvolution of these datasets, revealing novel insights into the unique drivers shaping advanced and lethal disease. In particular, large cohorts of patients with exposure to therapy with hormonal therapy has enabled the identification of specific genomic alterations that can promote resistance to hormonal therapy. This classification of genomic mechanisms of endocrine resistance has helped uncover the forces that shape the hormone dependence of ER+ breast cancer while also identifying new therapeutic targets with the promise to treat or even prevent endocrine resistant disease. In this presentation, we will review the genomic features of endocrine resistance metastatic breast cancer, detail evidence for (or against) specific alterations as likely mechanisms of resistance to endocrine therapy and describe next steps for clinical utilization of genomic information for the management of this disease.

Citation Format: P Razavi. The genomic landscape of endocrine-resistant metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES4-3.
Abstract ES5-2: Regional Management of the Axilla prior to Systemic Therapy
Authors: Pilewskie M
Published: March 2020

There is growing interest in personalizing axillary management strategies based on anatomic staging and receptor profile to minimize surgical morbidity and maximize oncologic outcomes. Axillary treatment decision making has become increasing complex given the variation in indications for axillary lymph node dissection (ALND) among clinically node negative patients based on treatment strategy. Current techniques to minimize the likelihood of requiring an ALND include application of the ACOSOG Z011 or AMAROS data for women undergoing surgery first or use of neoadjuvant chemotherapy (NAC) in attempts to downstage microscopic nodal disease. Hormone receptor positive, HER2 negative tumors have low pathologic complete response rates to NAC and therefore have low rates of axillary downstaging with this approach. We have evaluated the likelihood of requiring an ALND by receptor profile for differing management strategies. Given the low response rates to NAC among women with hormone receptor positive, HER2- tumors, use of NAC for this subtype is associated with a threefold increase in the receipt of ALND compared to those treated with upfront breast conserving surgery. In this session I will review the current strategies to minimize the likelihood of requiring an ALND among clinically node negative patients found to have a positive sentinel lymph node including application of the ACOSOG Z0011 and AMAROS strategies. I will also review the impact of axillary imaging and/or a positive lymph node needle biopsy on axillary surgery outcomes among clinically node negative patients. Having an understanding of these differing options will aid in personalizing axillary management recommendations to safely minimize the likelihood of ALND and the resultant risk of lymphedema.

Citation Format: M Pilewskie. Regional Management of the Axilla prior to Systemic Therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES5-2.
Abstract ES9-1: Discussing risk & uncertainty with patients in the context of GEP testing
Authors: Fallowfield L
Published: March 2020

Many discussions between physicians and their patients about the logic and rationale for different treatment recommendations are increasingly complex. The information required to aid educated decision-making requires careful balancing of the likely absolute benefits in terms of cure or preventing recurrence versus any treatment-related side effects. Few realise that medicine is an uncertain science where most facts are probabilities defined and refined by repeated hypothesis testing. In the context of life-threatening disease this can make communication with patients about risk and uncertainty challenging. Health literacy and numeracy skills in the general population are often poor, creating other communication difficulties; furthermore confusion increases when such conversations are set against a backdrop of fear and anxiety. Clinico-pathologic features traditionally help determine which women with early stage breast cancer are most likely to benefit from adjuvant chemotherapy, but many patients still believe that in life-threatening situations, more treatment must be better. Scores from gene expression profiling tests such as OncotypeDX®, EndoPredict® and Prosigna® may reduce some of the uncertainty and anxiety about omitting chemotherapy and increase the confidence of doctors helping patients with their decision-making.(1) However explaining high, intermediate and low risk test scores is not always straightforward especially when patients have widely varying personality and socio-educational characteristics. Both clinicians and their patients may also have a measurable intolerance to uncertainty that may contribute (irrespective of the recurrence score) to seemingly irrational decisions about treatment.

This interactive session will incorporate materials from Talking About Risk in the context of Genomic Testing (TARGET), an evidence-based program (2) funded by the BCRF- This includes didactic presentations (PPT) exercises and video clips of doctors explaining risk scores from genomic tests. After attending the session participants should:-

a) recognise how poor literacy and numeracy in general populations affects understanding about risk and decision-making b) understand how their own intolerance to uncertainty may ‘leak’ through into communication with patients and c) increase their repertoire of skills when explaining GEP scores to patients

References

1. L Fallowfield, L Matthews, S May, V Jenkins, D Bloomfield. Psycho-oncology (2018) 27:4, 1264-1269 https://doi.org/10.1002/pon.4664

2. Fallowfield, L., Solis-Trapala, I., Starkings, R. et al. Breast Cancer Res Treat (2019) 177: 641. https://doi.org/10.1007/s10549-019-05316-7

Citation Format: L Fallowfield. Discussing risk & uncertainty with patients in the context of GEP testing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES9-1.
Abstract ES9-2: Communicating risk information: talking by numbers
Authors: Jenkins V
Published: March 2020

Health literacy and numeracy skills amongst the general population are frequently poor, which impedes their understanding of important health information. Even those patients fully conversant with percentages and ratios can suffer with math anxiety when involved in stressful environments, making it difficult to process complex information effectively. This may be especially true for women with breast cancer having to decide about adjuvant treatments after receiving risk of recurrence genomic expression profiling (GEP) test results. Explaining risk of recurrence clearly can be a challenge for the clinician and nurse too. They need a wide repertoire of communication skills to accommodate the needs of patients with different social and educational backgrounds. Some health care professionals (HCPs) use analogies to explain risk, which may not always be of benefit. In order to help HCPs discuss GEP test results we developed and evaluated an educational program called TARGET (Talking About Risk in the Context of GEnomic Tests). As part of the evaluation we measured participants’ own numeracy skills and intolerance to uncertainty. In this talk the audience will be invited to participate in various numeracy exercises, and be able to compare their results with UK data from 56 breast cancer clinicians and 78 specialist breast care nurses. The presentation will conclude with suggestions of different ways to communicate risk.

Citation Format: V Jenkins. Communicating risk information: talking by numbers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES9-2.
Abstract MS2-1: Mechanisms of resistance to CDK4/6 inhibitors and new therapeutic approaches
Authors: Chandarlapaty S
Published: March 2020

Activation of the CDK4/6 kinases is a well-established mechanism whereby estrogens and other mitogens drive breast cancer growth. ATP competitive inhibitors of the CDK4/6 kinases have had a transformational impact on the clinical approach to ER+ breast cancer patients. However, with prolonged CDK4/6i therapy, most tumors ultimately develop resistance. Unlike the case for acquired resistance to many other targeted therapies, CDK4/6i resistance does not appear to be occur through mutations of the drug target. Second site, missense mutations in CDK4 and CDK6 have not been identified in either preclinical resistance screens or clinical biopsies of resistant tumors. This raises several questions including: (1) what are the genetic alterations and pathways that mediate resistance to CDK4/6i therapy in breast cancer, (2) what therapeutic approaches are effective after tumors have developed resistance to CDK4/6i, and (3) what can these understandings about resistance teach us about the underlying basis for sensitivity to CDK4/6i therapy. In this talk, published and unpublished data on mechanisms of resistance to CDK4/6i will be reviewed to elucidate how tumors can either restore CDK4/6 activity or else bypass the requirement for these G1 checkpoint kinases. Data on potential vulnerabilities for each class of drug-resistant tumors will then be discussed. Finally, the findings on resistance will be used to revisit the original understandings on the basis for CDK4/6i sensitivity and how that informs the ongoing use of these drugs in other settings and with more effective combinations that might suppress the emergence of resistance.

Citation Format: S Chandarlapaty. Mechanisms of resistance to CDK4/6 inhibitors and new therapeutic approaches [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS2-1.
Abstract OI: Novel non-canonical functions of EZH2 in triple negative breast cancer
Authors: Kleer CG
Published: March 2020

Patients with distant metastasis at the time of diagnosis have significantly worse prognosis. Triple negative breast carcinomas (TNBC) are heterogeneous tumors with propensity to metastasize and a guarded short term prognosis. The link between breast cancer and regulators of cell type identity was demonstrated in 2003, when enhancer of zeste homolog 2, EZH2, was reportedly overexpressed in approximately 55% of breast cancer tissue samples and was significantly associated with estrogen receptor negative status and worse disease free and overall survival. As the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), the methyltransferase EZH2 deposits trimethyl marks on histone tails of lysine 27 of histone H3 (H3K27me3) to effect transcriptional repression. However, in a subset (~ 30%) TNBC high levels of EZH2 are associated with low H3K27me3, suggesting the intriguing possibility that in this group of tumors EZH2 may promote progression through other unknown mechanisms. Recent studies have shown that in TNBC EZH2 may indeed function independent of PRC2 and H3K27me3 activity. During breast cancer initiation, EZH2 enhances breast cancer stem cells and mammary tumor development through transcriptional activation of NOTCH1 and upregulation of its signaling pathway. More recent data show that EZH2 protein binds to p38 MAP kinase with resulting EZH2 phosphorylation at threonine 367 and accumulation in the cytoplasm of TNBC cells. In breast cancer tissue samples, cytoplasmic pEZH2 T367 is significantly associated with low H3K27me3 levels and a triple negative phenotype. Mechanistically, pEZH2 T367 protein binds to cytoplasmic regulators of cell migration and invasion, and is required for metastasis. These studies demonstrate a H3K27me3-independent mechanism of EZH2 function in TNBC progression. Future investigations will be required to test the therapeutic potential of inhibiting EZH2 non-canonical mechanisms alone or in combination with pharmacological targeting of EZH2 methyltransferase activity in TNBC.

Citation Format: CG Kleer. Novel non-canonical functions of EZH2 in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OI.
Abstract OT1-01-04: A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy
Authors: McArthur Heather , Comen Elizabeth , Bryce Yolanda , Solomon Stephen B , Leal Jorge , Rodine Micaela , Abaya Christina DiLauro , Patil Sujita , Page David , Norton Larry
Published: March 2020

Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this randomized phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo versus standard care in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse.

Methods: Eligible pts are ≥18y, with ER <10%, PR <10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 160 pts will be randomized to one of two arms: breast surgery (control arm) or ipi/nivo/cryo followed by breast surgery and adjuvant nivo (intervention arm). Pts in the intervention arm will undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity.

Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen B Solomon, Jorge Leal, Micaela Rodine, Christina DiLauro Abaya, Sujita Patil, David Page, Larry Norton. A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-04.
Abstract OT1-01-05: AIPAC (Active Immunotherapy PAClitaxel): A randomized, double blind, placebo controlled, multinational phase IIb trial evaluating the efficacy of eftilagimod alpha (a soluble LAG-3 fusion protein) in combination with paclitaxel in hormone receptor positive metastatic breast cancer
Authors: Dirix Luc , Wildiers Hans , Huizing Manon T , De Cuypere Eveline , Schröder Carolina P , Armstrong Anne C , Huober Jans , Marmé Frederik , Schneeweiss Andreas , Khan Sarah , Triebel Fréderic
Published: March 2020

Background: Eftilagimod alpha (efti, previously IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Efti may lead to the activation of the dendritic cell network and to a strong anti-tumor CD8 T cell response when injected s.c. after chemotherapy at a time when these APC are loaded with tumor antigens. AIPAC (Active Immunotherapy PAClitaxel; NCT02614833) is a Phase IIb trial in hormone receptor (HR)-positive metastatic breast carcinoma patients receiving efti or placebo as adjunctive to weekly paclitaxel as a first-line chemotherapy. The randomized double blinded part (stage 2) has finished recruitment in June 2019. Primary analysis is expected Q1 2020.

Methods: This clinical trial is a placebo-controlled, double-blind, 1:1 randomized Phase IIb study aimed to enrol 226 patients at multiple centres across 7 different European countries. Patients with metastatic, HR-positive breast adenocarcinoma receiving first line chemotherapy with weekly paclitaxel and with measurable disease according to RECIST 1.1 are eligible. Patients suitable for Her2/neu targeted therapy are excluded from the trial. In the first treatment phase, paclitaxel (80 mg/m² IV at D1, D8, D15 plus efti (30 mg s.c.) or placebo at D2, D16 will be administered for 6 cycles (1 cycle = 4 weeks). This is followed by a maintenance phase in which stable or responding patients will receive efti or placebo for up to additional 52 weeks (12 injections). The primary endpoint is progression-free survival (PFS) by blinded independent central imaging review. Secondary endpoints include PFS by local assessment, overall survival, tumor response according to RECIST 1.1., time to and duration of response, duration of stable disease and quality of life.

Citation Format: Luc Dirix, Hans Wildiers, Manon T Huizing, Eveline De Cuypere, Carolina P Schröder, Anne C Armstrong, Jans Huober, Frederik Marmé, Andreas Schneeweiss, Sarah Khan, Fréderic Triebel. AIPAC (Active Immunotherapy PAClitaxel): A randomized, double blind, placebo controlled, multinational phase IIb trial evaluating the efficacy of eftilagimod alpha (a soluble LAG-3 fusion protein) in combination with paclitaxel in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-05.
Abstract OT2-04-01: A prospective, multicentre, open-label, randomized phase II study of PEmbroLizumab in combination with neo-adjuvant (F)EC-paclitaxel regimen in HER2-negative Inflammatory breast CANcer
Authors: Gonçalves Anthony
Published: March 2020

Background: Inflammatory breast cancer (IBC) represents a rare but aggressive form of locally advanced BC. In spite of multimodality therapy including neoadjuvant chemotherapy (NAC), radical surgery and radiotherapy, prognosis remains poor, notably in HER2-negative subtypes. Whole-genome and gene expression profiling studies in IBC have identified an immune-enriched signature predicting for pathological complete response (pCR), suggesting a critical role for T-cell cytotoxicity in reaching complete tumor cell elimination after NAC. In addition, overexpression of programmed cell death ligand 1 (PD-L1) mRNA in IBC is more frequent than in non-IBC and has significant correlation with pCR. Pembrolizumab (PEM), an anti- programmed cell death 1 (PD 1) receptor antibody, inhibiting its interaction with PD-L1, is registered or in development across a large range of malignancies. PEM may boost anti-tumor immunity, eradicating residual tumor cells and thus improving pCR and outcome in HER2-negative IBC.

Trial design: PELICAN-IPC 2015-016 trial (NCT03515798), sponsored by Institut Paoli-Calmettes with financial support of MSD, is a multicenter, randomized phase II, non-comparative study evaluating the addition of PEM to anthracyclines/taxanes NAC in non-metastatic HER2-negative IBC. Patients will receive 4 cycles of Q3W FEC100 (5FU 500 mg/m², Epirubicin 100 mg/m², Cyclophosphamide 500 mg/m²; non-triple negative) or 4 cycles of Q2W EC (Epirubicin 90 mg/m², Cyclophosphamide 600 mg/m²; triple-negative) followed by Q1W paclitaxel 80 mg/m² x 12, with (arm B) or without (arm A) Q3W IV PEM 200 mg started with C2 FEC/EC. The primary endpoint will be pCR in the experimental arm. The study also includes a run-in safety phase. Secondary endpoints include tolerance, invasive disease-free, event-free and overall survivals in each arms and collection of pre- and post-treatment tissue and blood samples for pharmacodynamics measurements and biological correlates. Following Simon’s 2-stage optimal procedure a total of 54 patients in arm B is required to reject the null hypothesis of a truly ineffective experimental arm (H0: p<= 20%) with 5% error risk and 90% power assuming a true pCR rate of 40%. 27 additional patients will be enrolled in the control arm A. Since June 2018, 7 patients have been enrolled in a single center and 13 additional centers are expected to open before the end of 2019.

Citation Format: Anthony Gonçalves. A prospective, multicentre, open-label, randomized phase II study of PEmbroLizumab in combination with neo-adjuvant (F)EC-paclitaxel regimen in HER2-negative Inflammatory breast CANcer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-01.
Abstract OT3-14-01: GERA: A health economic trial to analyze the impact of ehealth in breast cancer care
Authors: Eggersmann Tanja , Riese Christoph , Wenzel Claudia , Schinkoethe Timo , Degenhardt Tom , Wuerstlein Rachel , Harbeck Nadia , Welslau Manfred
Published: March 2020

Background: In breast oncology, the increasing number of oral drug therapies pose great challenges for patient management. Numerous studies demonstrate that well-informed patients develop higher confidence in their treatment and a greater sense of disease control, resulting in increased adherence and persistence as well as potentially better outcome. Patients need knowledge, skills and confidence to actively participate in their own care. Moreover, such skills also contribute to reduction of planned and unplanned visits and of accompanying a time expenditure of the practice staff, thus lowering the costs of the whole treatment. Enhanced quality of life also affects financial resources by reducing sick leaves at work. The electronic Patient Reported Outcome (ePRO) tool CANKADO is designed to help oncologists to bridge the gap between good, personalized care and a time and resource-saving treatment for cancer patients. CANKADO helps patients and their physicians regarding therapy management by a standardized documentation procedure and, if needed, direct feedback to patients by the integrated Pro-React system. Methods: Aim of GERA is to assess the economic impact of an ePRO tool in breast cancer care. It is a prospective, single arm, non-interventional trial, based on questionnaires that answered by patients via the CANKADO Patient App. All patients undergoing systemic therapy for breast cancer with access to CANKADO will be included in the evaluation. This study will take place in 10 German centers and 337 patients will be included in the study. The enrollment phase of patients will last 6 months, while the individual patient observation and accompaniment phase through CANKADO will continue for 3 months. Primary objective is to gain knowledge on the health economic impact of CANKADO resource utilization in breast cancer care including the evaluation of physicians’ time and patient experience. As secondary objectives, exploratory analysis of all collected information is planned. This includes the socio-demographic patient information, clinical characteristics, quality-of life and patient documentation behavior. Results: The GERA trial is ongoing. Results will be presented at the conference. Conflict of interest: None declared

Citation Format: Tanja Eggersmann, Christoph Riese, Claudia Wenzel, Timo Schinkoethe, Tom Degenhardt, Rachel Wuerstlein, Nadia Harbeck, Manfred Welslau. GERA: A health economic trial to analyze the impact of ehealth in breast cancer care [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-14-01.
Abstract P1-01-05: Intraoperative three-dimensions MiniiSCANR for determine adequate margin in breast cancer specimens before histopathological examination
Authors: Laohawiriyakamol Suphawat , Wangkulankul Piyanun , Woodtichartpreecha Piyanoot , Puttawibul Puttisak
Published: March 2020

Background: 20-30% of breast conserving surgery patients undergo a second re-excision procedure due to tumor-positive margins at final histopathology. Various modalities are used to assess the adequacy of surgical resection to minimize positive margin and reoperation rates. MiniiSCAN™ is a method of intraoperative specimen radiography that allows for margin evaluation following excisional breast lesion either BI-RADS 4 and 5. The mechanism of MiniiSCAN™ is similar to computer tomography but specimen is rotated on the plate instead circular rotating frame with an x-ray tube mounted on 1 side and a detector on the opposite side in conventional computerized tomography scan. It is easily and short time to reconstructed into 3 dimensions. This machine was developed by Songklanagarind hospital and National Science and Technology Development Agency, Thailand.

Objective: To evaluate the efficacy of MiniiSCAN™ as a surgical margin guidance tool compared with pathological margin in breast cancer specimens.

Materials & Methods: A retrospective review was designed, 62 consecutive cases of abnormal mammogram (BI-RADS 4,5) with or without wire localization from 1 June 2016 to 30 June 2019 were identified from the electronic medical records at Prince of Songkla University.

Results: Of the 62 specimens imaged, 17 had invasive cancer and ten had in-situ pathological diagnoses. Of these, 10 patients had a positive tumor margin and 17 a negative tumor margin at final histopathology. Margin status evaluation by MiniiSCAN™ reconstruction were calculated in 4 minutes (acquisition and reconstruction time). Of the 27 specimens readings, the margin status in 24 patients was correctly predicted by MiniiSCAN™. There were two false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of MiniiSCAN™ in margin status prediction were 88.89%, 80%, 94.11%, 88.89% and 88.89%, respectively.

Conclusion: MiniiSCAN™ could be integrated into routine care, enabling the surgical team to perform and interpret specimen radiographs rapidly and make immediate surgical decisions.

Keywords: Abnormal mammography, Breast cancer, CT scan, Specimen radiography

Citation Format: Suphawat Laohawiriyakamol, Piyanun Wangkulankul, Piyanoot Woodtichartpreecha, Puttisak Puttawibul. Intraoperative three-dimensions MiniiSCANR for determine adequate margin in breast cancer specimens before histopathological examination [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-05.
Abstract P1-01-08: Optical metabolic imaging of the effects of acute and intermittent hypoxia in murine breast cancer cells
Authors: Rebello Lisa , Rajaram Narasimhan
Published: March 2020

About 90% of the patients diagnosed with breast cancer succumb due to metastases and not from primary tumor. There are currently few methods that can distinguish indolent and aggressive breast tumors. Recent studies have shown differences in the metabolic profiles of primary, circulating, and metastatic breast cancer cells. One of the key regulators of metastases in breast cancer is the transcription factor Twist. The goal of our study was to determine the relationship between Twist expression and cellular metabolism, and the effect of this relationship on metastatic potential. Multiphoton microscopy can provide non-invasive, label-free and reproducible measurements of cellular metabolism. An optical redox ratio of endogenous fluorescence from nicotinamide adenine dicnucleotide (NADH) and flavin adenine dinucleotide (FAD) (calculated as FAD/NADH+FAD) can reflect the balance between mitochondrial oxidative phosphorylation and glucose catabolism in the cell. Because hypoxia is known to promote metastasis, we studied the effect of both intermittent and acute hypoxia on cellular metabolism in 4T1 murine breast cancer cells. We generated a 4T1-Twist− cell line using CRISPR-Cas9 technology. Western blots of Twist protein expression confirmed that Twist expression was significantly lower in the selected cell population compared with the parental 4T1 line. Both cell lines were exposed to 0.5% oxygen for 3 hours and one hour of reoxygenation (acute hypoxia), and 3 cycles of one-hour hypoxia followed by one-hour reoxygenation (intermittent hypoxia). Multiphoton imaging of endogenous fluorescence as well as metabolic flux analysis (Seahorse Biosciences) was performed for both hypoxic exposures in both cell lines. Our results indicate a significant increase in the optical redox ratio in 4T1 cells when exposed to acute hypoxia, indicating a possible increase in oxidative metabolism. There were no signfiicant differences in the 4T1-Twist− line. On the other hand, we observed a decrease in the optical redox ratio in response to intermittent hypoxia in the 4T1 cells and the opposite effect in the 4T1-Twist− line. In addition to these cell lines, we will also present data from sibling cell lines of the 4T1 with varying Twist levels and hence metastatic potential. These data indicate indicate potentially measurable metabolic differences between indolent and aggressive breast cancer cells when subject to a hypoxia-reoxygenation regimen.

Citation Format: Lisa Rebello, Narasimhan Rajaram. Optical metabolic imaging of the effects of acute and intermittent hypoxia in murine breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-08.
Abstract P1-03-05: Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer
Authors: Yu Chun I , Wu Te-Chia , Kim Kyung In , Menghi Francesca , Oliveira Vanessa , Marches Florentina , Liu Edison T , Banchereau Jacques , Palucka Karolina
Published: March 2020

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All eleven (11) analyzed to date PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among 11 PDX tumors tested, five did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastasis (lung and liver). Transcriptional profiling with RNAseq revealed significant differences in the immune landscape of primary and metastatic tumors. In particular, liver metastases were enriched in myeloid and plasma cell transcripts. Further analysis is ongoing to uncover specific pathways involved. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis.

Citation Format: Chun I Yu, Te-Chia Wu, Kyung In Kim, Francesca Menghi, Vanessa Oliveira, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-05.
Abstract P1-03-07: Investigation of combination treatment an aromatase inhibitor and anti-inflammatory treatment in a model of oestrogen receptor positive breast cancer
Authors: Dunbier Anita K , Hazlett Jody A , Powell Katelyn , Niemi Ginny , Kemp Roslyn
Published: March 2020

Background: Previous analysis has revealed that high pre-treatment expression of an inflammatory gene expression signature and lymphocytic infiltration are correlated with poor response to neoadjuvant aromatase inhibitor (AI) treatment1. Upon treatment with AIs, inflammatory gene expression also increases1. These changes are also seen in vitro where an increase in chemokine secretion has been observed upon oestrogen deprivation, suggesting that treatment with anti-oestrogen therapy may modulate the immune response. In addition, non-steroidal anti-inflammatory drug (NSAID) intake is associated with a significantly decreased risk of disease recurrence and breast cancer related death. In this study we set out to investigate the immunological response to AI treatment alone and in combination with NSAID treatment in an animal model of estrogen receptor positive (ER+ve) breast cancer.

Methods: A syngeneic immunocompetent murine ER+ breast tumour model was used in which SSM3 ER+ BrCa cells were injected into the mammary pad of wild-type 129SvEv mice. Once tumours reached a size of 49 mm2, mice were ovariectomised and treated with combinations of letrozole, celecoxib, aspirin and vehicle control. Tumours were measured for 25 days following treatment and tumours were analysed using flow cytometry and immunohistochemistry.

Results: Treatment with letrozole alone and letrozole + celecoxib resulted in a significant reduction tumour size after 25 days of treatment (p<0.001). Examination of the immune cell infiltrate of these tumours using flow cytometry determined that combination letrozole and celecoxib resulted in decreased numbers of CD11b+ cells compared to vehicle treated tumours (p = 0.02), and to celecoxib only treated tumours (p = 0.008). Working within recommended guidelines for assessing stromal TILs in H&E sections in a larger cohort (n=51), we determined that the percentage of stromal TILs increased in all treatment groups compared to the pre-treatment biopsy, and that the combination treatment had lower levels of TILs compared to vehicle treated tumours (p = 0.02).

Conclusions: We conclude that treatment of ER+ BrCa with letrozole induces an immune response in the tumour microenvironment which can be modulated by the addition of an NSAID. Our findings suggest that modulation of the immune response to endocrine therapy may have the potential to enhance response to treatment.

References: 1. Dunbier et al., 2013. Clin Cancer Res. 19:2775-86.

Citation Format: Anita K Dunbier, Jody A Hazlett, Katelyn Powell, Ginny Niemi, Roslyn Kemp. Investigation of combination treatment an aromatase inhibitor and anti-inflammatory treatment in a model of oestrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-07.
Abstract P1-03-09: The role of E2F5 in breast cancer progression and metastasis
Authors: To Briana , Andrechek Eran Robert
Published: March 2020

Advances in cancer genomics and transcriptomics have provided a better understanding of the diverse genetic landscape driving breast cancer pathogenesis. Despite these advances, the molecular drivers of triple negative breast cancer, an aggressive and heterogenous disease, remains highly elusive. Utilizing a genomic approach, we examined genetic differences across mouse models of breast cancer and identified a gene that was consistently deleted in basal-like mouse models, the predominant intrinsic subtype of triple negative breast cancer. Specifically, we identified a consistent deletion in the transcription factor E2F5. In human breast cancer, E2F5 activity and expression is associated with better overall survival and relapse free survival. To further study the role of E2F5 in breast cancer, E2F5 was deleted in the mammary gland of FVB mice (E2F5cKO) through the use of a cre-lox system driven by the MMTV promoter. E2F5cKO mouse demonstrated a delay a mammary outgrowth, suggesting a potential role in mammary gland development. E2F5cKO mice were aged and observed for tumor development. This revealed mammary tumor formation after an extended latency of 19 months. The resulting mammary tumors demonstrated diverse histological patterns. E2F5cKO tumors also demonstrate high metastatic potential with 70% of tumor bearing mice developing metastasis to the lung. In addition, E2F5cKO tumors have a propensity to metastasize to axillary lymph nodes when transplanted into MMTV-Cre mice, a unique feature that is not commonly observed in other mouse models of breast cancer. To begin to understand the mechanism of tumor progression in E2F5cKO mice, differential gene expression was performed on gene expression data derived from E2F5 or GFP overexpression Human Mammary Epithelial Cells. The resulting differentially expressed genes were further filtered based on fold change, established role in cancer, potential E2F binding site and gene ontology. One of the leading candidates that arose from this analysis was KRas, an oncogene that is highly implicated in tumorigenesis. KRas expression negatively correlated with E2F5 expression. Using a bioinformatic approach, we demonstrated that this inverse relationship between KRas and E2F5 appears to be conserved in human breast cancer. Given this inverse relationship between E2F5 and KRas, we postulate that E2F5 deletion in the mammary gland of mice leads to increased KRas activity. Consistent with our hypothesis, western blot analysis revealed high activity in two major KRas signaling pathways, Akt and Erk, in the majority of E2F5cKO tumors. Together, this preliminary data suggest that E2F5 may behave as a tumor suppressor by negatively regulating the oncogene KRas.

Citation Format: Briana To, Eran Robert Andrechek. The role of E2F5 in breast cancer progression and metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-09.