bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-08-72: Poor prognosis in elderly patients with breast cancer resulted from under-treatment in patients with triple negative breast cancer and mortality from other than breast cancer
Authors: Moon Gilseong , Ko Ji wool , Noh Hany , Cho In-Jeong , Lee Jong-in , Han Airi
Published: March 2020

Background: Breast cancer is the leading cause of malignant disease in Korean women nest to thyroid cancer. Age is one of the significant risk factor and Korean population is aging rapidly, almost 1.5 times older than a half century ago, from 52.4 years in 1960 to 78.5years at 2005. While it is uncertain the proportional incidence is also increasing, absolute number of elderly patients is increasing and unmet clinical needs and unanswered questions are remained in the clinical practice for elderly patients. The aim of this study is to outline breast cancer in elderly patients and examine survivals by clinicopathologic factors such as age, stage and disease subtype.

Material and Methods: Patients who were diagnosed and completed their primary treatment for breast cancer from 2000 to 2013 were included. Clinicopathologic data was collected with retrospective data review and survival data and risk factors, if the survival was statistically significant, were obtained.

Results: 1103 patients with invasive breast cancer were included. Mean age was 52.71±11.478(22-89). Subjects were divided into three group, <40 (n=147, 35.9±3.704), 40-60 (n=680,49±5.131), >60(n=276,68.6±5.62). Patients over 60 had statistically worse overall survival(p=0.011) and distant disease free survival(p=0.012) with Kaplan-Meier method with log rank test and hazard ratio(HR) of elderly was 2.206 with 1.046-4.658 96% Confidence Interval(CI). For the worse prognosis of elderly, triple negative breast cancer who got less than standard systemic treatment (HR=4.836, 95% CI, 1.514-15.452) and mortality from other than breast(HR=2.395, 95% CI,1.106-5.188) cancer were significantly correlated with higher mortality in elderly patients.

Conclusion: Elderly patients with breast cancer experience significant worse survival when they got less than standard systemic treatment or second primary disease other than breast cancer in their follow up period.

Citation Format: Gilseong Moon, Ji wool Ko, Hany Noh, In-Jeong Cho, Jong-in Lee, Airi Han. Poor prognosis in elderly patients with breast cancer resulted from under-treatment in patients with triple negative breast cancer and mortality from other than 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 P3-08-72.
Abstract P3-10-13: Rac inhibition as an alternative approach to treating hormone dependent breast cancer
Authors: Goka Erik T , Sun Jun , Lopez Dayrelis T Mesa , Lippman Marc E
Published: March 2020

Hormone positive breast cancer remains one of the leading causes of cancer mortality in women. Despite the advancement in endocrine therapy and the addition of cyclin dependent kinase (CDK) 4/6 inhibitors, patients eventually become refractory to treatment creating a desperate need for the development of alternative therapies. Previously, we discovered HACE1, the E3 ubiquitin ligase that targets the small GTPase Rac1 for proteasomal mediated degradation. HACE1 is commonly lost in estrogen receptor (ER) positive and HER2 positive breast cancers and results in the hyperactivation of the Rac signaling pathway. Here, we show that Rac1 resides in the estrogen receptor transcriptional complex and acts as a critical estrogen receptor transcriptional co-activator. The dependency of Rac on ER transcription is further exemplified by the treating ER+ breast cancer cells with a Rac inhibitor where transcriptional profiling identified ER target genes were preferentially down-regulated. Thus, we confirm the dependency of Rac1 in ER+ breast cancers and show that Rac1 is necessary for estrogen receptor transcriptional activity. Importantly, we show that a novel Rac1 inhibitor is capable of reducing estrogen receptor transcriptional activity as well as impairing cellular proliferation and migration. Moreover, Rac inhibition is shown to enhance the anti-tumor effects of fulvestrant both in vitro and in vivo, including in a patient-derived-xenograft (PDX) model of ER+ disease. Lastly, we demonstrate that the administration of a novel Rac inhibitor is well-tolerated after chronic dosing in both small and large animal species. Together these data suggest a new potential pathway for treating hormone dependent breast cancer.

Citation Format: Erik T Goka, Jun Sun, Dayrelis T Mesa Lopez, Marc E Lippman. Rac inhibition as an alternative approach to treating hormone dependent 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 P3-10-13.
Abstract P3-11-21: Identification and characterization of novel splice variants in triple-negative breast cancer
Authors: Arun Gayatri , Dhingra Priyanka , Munch Robin , Fredrick Vanessa , Akerman Martin
Published: March 2020

Splicing deregulation is a major hallmark of cancer, affecting progression, metastasis and therapy resistance. Multiple studies have demonstrated the oncogenic activity of specific splicing events and splicing factors, including SRSF1, SRSF2, ESRP1, and RBFOX1, in human and animal models. As such, cancer-associated splicing deregulation may be a novel source of clinically-applicable biomarkers and therapeutic targets, particularly for treatment-insensitive cancers such as TNBC. Here, we identified and experimentally characterized novel splicing changes in triple negative breast cancer by analyzing TCGA breast cancer RNA-seq data using our software platform SpliceCore. SpliceCore integrates machine learning (ML) algorithms with high-performance computing to analyze large RNA-Seq datasets to predict biologically relevant splicing events. Our analysis of TCGA BRCA datasets has revealed several previously unknown splicing events specific to TNBC patient cohorts, that is subsequently experimentally validated in TNBC cell lines. We provide biological evidence for such TNBC specific splice-switch both at the RNA and protein level. We provide evidence for SpliceCore predicted splice-switching oligonucleotides (SSO) and verify their biological activity in TNBC cell lines. Further, functional studies using potent and specific SSOs against the top candidates reveal a critical role for some of these novel isoforms in TNBC. Together, we provide a proof of concept study using SpliceCore to identify, design, and target novel splicing changes for subsequent clinical translation and therapeutic development.

Citation Format: Gayatri Arun, Priyanka Dhingra, Robin Munch, Vanessa Fredrick, Martin Akerman. Identification and characterization of novel splice variants 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 P3-11-21.
Abstract P4-01-09: Phenotypic profiling of circulating tumor cells (CTCs) in patients with metastatic breast cancer reveals clinically-relevant heterogeneity in CTC morphology and marker expression
Authors: Pramparo Tiziano , Jendrisak Adam , Ontiveros Priscilla , Kearney Megan , Chu Lincy , Ebrahim Nadia , Schonhoft Joseph , Wenstrup Rick , Wang Yipeng
Published: March 2020

Background: The choice between hormonal therapies and chemotherapy is a frequent decision in the standard of care of metastatic breast cancer (mBCa) patients. We previously developed quantitative measures of phenotypic CTC heterogeneity in metastatic prostate cancer and found that higher heterogeneity was associated with better survival on chemotherapy vs. targeted hormonal therapies in a risk adjusted analysis (Scher et al. 2017 Cancer Research). Here we sought to test the feasibility of measuring CTC heterogeneity in mBCa patients.

Methods: 295 blood samples from 165 pts (84 HR+, 19 Her2+, 8 HR+/Her2+, 54 TNBC) from mBCa patients were processed for CTC analysis utilizing the Epic Sciences Functional Cell Profiling platform. Following enumeration, multi-dimensional phenotypic characterization analysis was performed utilizing protein expression and digital pathology features. Features from each CTC (3994 CTCs from 165 pts, were compared by unsupervised clustering to assess intra-patient CTC heterogeneity among mBCa CTC phenotypes.

Results: CTCs were detected in 76.9% (227/295) of mBCa patients (med=2.4 CTC/mL, Range 0 - 747). Phenotypic profiling identified distinct CTC subtypes characterized by morphological and protein expression features that correlated with mBCa subtypes. Prevalent CTC features that associated with mBCa were either high cytokeratin (CK) expression or lower nuclear to cytoplasmic (N/C) ratio with lower CK expression. Analysis of mBCa subtypes showed that TNBC pts were characterized by CTCs with a large nuclear area and high CK expression. We observed marked differences in CTC heterogeneity across patients, with some patients having more uniform CTC profiles, and others having higher phenotypic diversity. mBCa subtypes had similar intra-patient heterogeneity level.

Conclusions: Distinct CTC phenotypes can be visualized and quantified across patients and associated with specific mBCa subtypes. Our analysis revealed significant heterogeneity between individual CTCs both between and within patients. Identification of patients with high heterogeneity may help to identify patients unlikely to respond to targeted therapies. Studies to link heterogeneity to efficacy of specific therapies and patient outcome are ongoing.

Citation Format: Tiziano Pramparo, Adam Jendrisak, Priscilla Ontiveros, Megan Kearney, Lincy Chu, Nadia Ebrahim, Joseph Schonhoft, Rick Wenstrup, Yipeng Wang. Phenotypic profiling of circulating tumor cells (CTCs) in patients with metastatic breast cancer reveals clinically-relevant heterogeneity in CTC morphology and marker expression [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 P4-01-09.
Abstract P4-01-14: Influence of radiotherapy on residual circulating epithelial tumor cells (CETCs) and their programmed cell death ligand 1 (PD-L1) status in breast cancer patients
Authors: Schott Dorothea , Pizon Monika , Pachmann Ulrich , Pachmann Katharina , Mäurer Matthias
Published: March 2020

Background: Preclinical studies have suggested that radiotherapy followed by immunotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation induces immunogenic changes in cancer cells which can lead to adaptive up-regulation of PD-L1 expression. Moreover, radiotherapy reduces not only local recurrence but even more distant relapse indicating its influence also on the residual occult tumor such as circulating tumor cells. For this reason the aim of this study was to determine the PD-L1 status on CETCs before and during radiotherapy.

Methods: CETCs were determined in 54 primary breast cancer patients in early and locally advanced stages. The number of CETCs and their expression of PDL-L1 were investigated using the maintrac method. The fraction of PD-L1 positive CETCs was assessed prior to (baseline), 3 and 6 weeks after the start of radiotherapy.

Results: We found an association between the PD-L1 status on CETCs and aggressiveness of cancer disease before radiotherapy. Patients with positive lymph node status had more PD-L1 positive CETCs as compared to patients with negative lymph nodes (mean 73 vs. 50, p<0.01). HER2 expression of the primary tumor was also positively correlated with PD-L1 expression. Lower numbers of CETCs were detected in patients who had not received chemotherapy or adjuvant chemotherapy before radiation than in those who received neoadjuvant chemotherapy (median 20 vs 25 vs 120 CETC/100µl blood, p<0.001). Surprisingly, the fraction of PD-L1 positive CETC decreased during radiotherapy only in patients who had received neoadjuvant chemotherapy.

Conclusion: The number of CETCs and the fraction of PD-L1 positive CETCs were higher in patients who had received neoadjuvant chemotherapy and radiotherapy reduced both measured biomarkers. In the future PD-1/PD-L1 checkpoint inhibitors after radiotherapy might have additional benefit in breast cancer patients.

Citation Format: Dorothea Schott, Monika Pizon, Ulrich Pachmann, Katharina Pachmann, Matthias Mäurer. Influence of radiotherapy on residual circulating epithelial tumor cells (CETCs) and their programmed cell death ligand 1 (PD-L1) status in breast cancer patients [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 P4-01-14.
Abstract P4-03-01: Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict the status of pathologic response
Authors: Große Regina , Lebioda Antonia , Saegenschnitter Jana , Nguyen Tin Dao , Zentgraf Holger , Buchmann Joerg , Fathke Christine , Steer Susanne , Thomssen Christoph
Published: March 2020

Introduction: Neoadjuvant breast cancer therapy trials have documented impressive rates of pathologic complete response (pCR) of up to 70% and above, depending on grade, hormone receptor and HER2 receptor status and type of therapy. The purpose of our prospective single institution trial is to examine the predictive value of a standardized vacuum assisted core-needle biopsy (VAB) of the tumor site after neoadjuvant therapy with respect to pathologic response status.

Methods: From 2011-2017, all patients who had completed neoadjuvant breast cancer therapy at our institution were informed about this trial regardless of their clinical response status. In case of consent, a VAB of the clip-marked tumor site was performed directly before the operation. At least 3, in most cases 6 biopsy cylinders were obtained.

Results: A total of 113 patients completing neoadjuvant therapy consented to the trial. Four patients presented with bilateral breast cancer, resulting in 117 cases of breast cancer. The pCR rate (ypT0ypN0) was 36% (n=42). In 14 cases, the biopsy did not show any sign of residual disease, although residual disease was detected upon operation, resulting in an accuracy of 88% for correct prediction of pathologic response. Pre-operative VAB correctly predicted residual tumor in 81%. The negative predictive value was 75%.

Conclusions: Although the results of this trial are encouraging, a false negative rate of 19% is entirely insufficient. The method may be useful in guiding decisions regarding the modification of neoadjuvant therapy based on pathological response. Whether or not correct prediction of pathologic response may be improved by further standardizing the tumor marking procedure as well as better defining and increasing the volume of tissue removal by VAB should be examined in a further prospective trial. The omission of operative therapy in case of pCR in a preoperative biopsy after completion of NACT cannot be recommended.

Citation Format: Regina Große, Antonia Lebioda, Jana Saegenschnitter, Tin Dao Nguyen, Holger Zentgraf, Joerg Buchmann, Christine Fathke, Susanne Steer, Christoph Thomssen. Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict the status of pathologic response [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 P4-03-01.
Abstract P4-06-10: Lentiviral signaling reporters uncover tumor-initiating cell heterogeneity in breast cancer patient-derived xenografts
Authors: Landua John , Gong Ping , Lewis Michael
Published: March 2020

Classical markers of tumor-initiating cells (TIC), aldehyde dehydrogenase 1 (ALDH1) activity and the cell-surface markers, CD44pos/CD24low/neg, show insufficient cell type specificity to identify TIC definitively, nor do they allow robust enrichment by FACS. As a consequence, analyses of TIC function and gene expression to date are not definitive. Identification and characterization of the TIC subpopulation is critically important in breast cancer since these cells are thought to mediate treatment resistance, as well as local and distant recurrence. This is particularly critical for “triple negative” breast cancer (TNBC), since currently there are no targeted therapies available for this clinical subtype. Lentiviral signaling reporter vectors allow purification of enriched TIC subpopulations thereby facilitating single cell analyses to identify distinct sets of cells with TIC features. We used a collection of fluorescent lentiviral reporters that enable visualization and flow cytometric enrichment of cells undergoing STAT3-, GLI-, WNT-, or OCT4/SOX2-mediated transcriptional activity. Our collection of patient derived xenograft (PDX) models of TNBC were infected with the lentiviral reporters, re-transplanted, and screened for reporter activity upon regrowth. TIC function of reporter-expressing cells relative to negative cells was assayed by mammosphere formation and limiting dilution transplantation. Reporter expressing cells with enriched TIC function were then analyzed by single cell RNAseq for expression of classical markers to identify the subset of cells most likely to represent the TIC subpopulation. Our results indicate that STAT3 and GLI transcriptional activity can serve as uniquely PDX-dependent indicators for TIC function for a subpopulation of cancer cells. Also, multiple potential TIC signaling pathways, including STAT3, GLI, and OCT4/SOX2, can be active in a single PDX model, but do not necessarily associate with TIC function, indicating TIC diversity in TNBC. These data in conjunction with treatment response and single-cell RNA-seq sheds light on the molecular diversity of TIC populations in TNBC, identifies candidate targets for therapeutic intervention, and will indicate whether TIC diversity is associated with differential response to different chemotherapeutic agents.

Citation Format: John Landua, Ping Gong, Michael Lewis. Lentiviral signaling reporters uncover tumor-initiating cell heterogeneity in breast cancer patient-derived xenografts [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 P4-06-10.
Abstract P4-08-03: Tumor suppressors p53 and ARF control ADAR1-driven tumorigenicity in triple negative breast cancer
Authors: Kung Che-Pei , Kuzmicki Catherine E , Bross Emily A , Ryu Sua , Freeman Eric , Sabloak Thwisha , Bramel Emily R , Maggi Leonard B , Weber Jason D
Published: March 2020

Research Overview and Objective Triple-negative breast cancer (TNBC) accounts for one-fifth of the breast cancer patient population. The heterogeneous nature of TNBC and lack of options for targeted therapy make its treatment a constant challenge. The co-deficiency of tumor suppressors p53 and ARF is a significant genetic signature enriched in TNBC, but it is not yet clear how TNBC is regulated by this genetic alteration. Methods To answer this question, we established p53/ARF-defective murine embryonic fibroblast (MEF) to study the molecular and phenotypic consequences in vitro. Moreover, transgenic mice were generated to investigate the effect of p53/ARF deficiency on mammary tumor development in vivo. Results Increased transformation capability was observed in p53/ARF-defective cells, and formation of aggressive mammary tumors was also seen in p53−/−ARF−/− mice. RNA-editing enzyme ADAR1 was identified as a potential mediator for the elevated oncogenic potential. Interestingly, we found that the overexpression of ADAR1 is also prevalent in human TNBC cell lines and patient specimen. Using short hairpin RNA (shRNA) to reduce ADAR1 expression abrogated the oncogenic potential of human TNBC cell lines, while non-TNBC cells are less susceptible. Different levels of RNA editing of known ADAR1 targets were detected in shRNA-treated human TNBC cell lines, suggesting that ADAR1-mediated RNA editing contributes to TNBC pathogenesis. Implication/Discussion These results indicate critical roles played by the tumor suppressors p53 and ARF in the pathogenesis of TNBC, partially through affecting ADAR1-mediated RNA editing. Further understanding of this pathway could shed light on potential vulnerabilities of TNBC and inform the development of personalized therapies based on patients’ genetic signiatures.

Citation Format: Che-Pei Kung, Catherine E Kuzmicki, Emily A Bross, Sua Ryu, Eric Freeman, Thwisha Sabloak, Emily R Bramel, Leonard B Maggi Jr, Jason D Weber. Tumor suppressors p53 and ARF control ADAR1-driven tumorigenicity 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 P4-08-03.
Abstract P4-14-06: Express model of hereditary multigene mutation analysis in breast cancer patients
Authors: Grinshpun Albert , Carmon Einat , Kaduri Luna , Zick Aviad , Shkedi Shiri , Shalom Edna , Granit Avital , Monas Liza , Shaldovsky Tamar , Hamburger Tamar , Meiner Vardiella , Peretz Tamar
Published: March 2020

Introduction

Traditionally, women with family history of breast and ovarian cancer, or young age at presentation, are referred to BRCA1\2 mutation testing. The growing information regarding other genes involved in predisposition to breast cancer (regardless of specific family history) and the potential impact of germline alterations on surgical and oncologic management led us to establish a model to perform a quick multigene mutation evaluation among breast cancer patients at our cancer institute.

Methods

All breast cancer patients that required genetic counselling (according to treating oncologist/surgeon’s judgement) were referred, after thorough explanation and signing informed-consent forms, to a 'genetic coordinator' and 'genetic nurse'. They provided each patient with a second pre-test explanation and ordered wide hereditary cancer gene panel (83-genes, Invitae). Results were given within 2-4 weeks. All patients\results were registered centrally at our center and discussed at routine Onco-genetic Multidisciplinary Board (OMB). A referral for formal genetic counselling is offered to all patients, and rapid track is arranged for patients with positive results.

Results

During a 12-months pilot period, 130 breast cancer patients were examined via the model, and 109 results were received; 44 patients (41%) had no abnormal findings, 50 patients (45%) had variants of uncertain clinical significance, and 15 patients (14%) were found carriers of pathogenic variants (ATM n=2, BRCA1 n=1, BRCA2 n=2, CHEK2 n=3, MUTYH n=1, PALB2 n=2, RAD50 n=1, RECQL4 n=1, TP53 n=2). Among this group, 3 patients (20%) had immediate panel-driven treatment decisions: Mastectomy to avoid radiotherapy (RAD50 carrier), oophorectomy during lumpectomy (BRCA2 carrier), and bilateral risk-reducing mastectomy instead of lumpectomy (TP53 carrier).

Conclusions

The creation of an Express-model for broad germline analysis allows to obtain rapid and meaningful results with impact on treatment. We believe that the Express-model should be considered as an integral tool of multimodal care of breast cancer patients.

Citation Format: Albert Grinshpun, Einat Carmon, Luna Kaduri, Aviad Zick, Shiri Shkedi, Edna Shalom, Avital Granit, Liza Monas, Tamar Shaldovsky, Tamar Hamburger, Vardiella Meiner, Tamar Peretz. Express model of hereditary multigene mutation analysis in breast cancer patients [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 P4-14-06.
Abstract P4-14-09: Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis
Authors: Saleh Ramy , Nadler Michelle B , Desnoyers Alexandra , Fazelzad Rouhi , Amir Eitan
Published: March 2020

Background: The addition of platinum agents to anthracycline and taxane-based chemotherapy in early-stage triple negative breast cancer (TNBC) patients improves pathological complete response (pCR). Long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), have not been well-established.

Methods: A systematic literature review identified studies using platinum-based treatment in TNBC patients in the neoadjuvant or adjuvant setting with reportable long-term outcomes. Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on treatment setting (neoadjuvant vs. adjuvant) and study design (retrospective vs. randomized controlled trials). When available, odds ratios (OR) for commonly reported safety and tolerability measures such as treatment-related death, treatment discontinuation without progression, dose reduction, neuropathy, renal impairment and hematological toxicity were calculated.

Results: Seven studies comprising 1699 patients met the inclusion criteria. Median follow up was 54.5 months. All studies reported DFS and 4 studies reported OS. DFS was significantly better in platinum-based treatment (HR 0.71, 95% confidence interval (CI) 0.53-0.96; P = 0.03). However, OS was no different with a higher number of events in the platinum-based treatment arm (HR 1.17, 95% CI 0.81-1.69; P = 0.42). There was no significant difference between treatment settings (p = 0.74) or between study designs (p = 0.74), although a higher HR for OS was observed for studies in the adjuvant (HR 1.34, 95% CI 0.54-3.35) compared to neoadjuvant setting (HR 1.14, 95% CI 0.76-1.70). The reporting of toxicity was suboptimal with most studies not reporting safety and tolerability metrics clearly. Platinum-based treatment was associated with more neutropenia and thrombocytopenia and treatment discontinuation, however, the magnitude of this effect could not be estimated accurately.

Conclusions: Platinum-based treatment improves DFS but has no effect on OS and increases toxicity. The discordant effect of platinum-based treatment on DFS and OS suggest the potential development of platinum resistance and worse outcomes after recurrence. The higher magnitude of discordance in adjuvant compared to neoadjuvant studies suggests an effect of platinum-based therapy on loco-regional control prior to surgery rather than prevention of distant metastatic disease. Platinum-based chemotherapy cannot be recommended in unselected patients with TNBC.

Citation Format: Ramy Saleh, Michelle B Nadler, Alexandra Desnoyers, Rouhi Fazelzad, Eitan Amir. Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis [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 P4-14-09.
Abstract P5-04-27: The relationship between tumour associated macrophage markers and tumour, demographic & behavioural factors in breast cancer
Authors: Singh Urvashi , Castle John , Greenhalgh Sophie , Hussain Umar , Descamps Tine , Nash Sarah , Wilson Mary , Hunt Roger , Kirwan Cliona C
Published: March 2020

BACKGROUND: Tumour associated macrophages (TAMs) are prognostic markers in breast cancer, however the influence of patient demographic and behavioural factors on these inflammatory markers has not been fully appreciated.

METHODS: In 201 invasive breast cancer and 58 ductal carcinoma in-situ (DCIS) patients, TAM density (percentage % CD68 [IHC-immunohistochemistry] positive cells) was correlated with tumour factors (grade, proliferation (Ki67), ER, HER2); demographic factors (age, menopausal status, breast density, BMI, diabetes) and behavioural factors (smoking, alcohol).

RESULTS: TAM density was increased in invasive breast cancer, compared to DCIS, and normal tissue distant from the tumour (59%, 41% and 6% respectively; p<0.001). In invasive cancer, TAM density increased with increasing tumour grade (Grade 1: 42%, Grade 2: 58%, Grade 3: 72%; p=0.006), high Ki67 (71% vs. 47%; p=0.004), ER negativity (70% vs. 51%; p=0.02) and HER2 (HER2 positive 77% vs. HER2 negative 55%; p=0.055). TAM density was higher in high compared to low/intermediate DCIS (44% % vs 31% respectively).

In terms of demographic factors, TAM density did not correlate with age, menopausal status, breast density (BIRADs), BMI or history of diabetes. TAM density was not increased in patients who smoked; however, it was increased in patients who self-reported alcohol intake (non-drinker 43% vs. drinker 62%; p=0.01).

CONCLUSION: TAM density shows utility in identifying aggressive breast cancer sub-types. The association reported between TAM density and alcohol intake suggests a possible mechanism for alcohol as a risk factor for breast cancer.

Citation Format: Urvashi Singh, John Castle, Sophie Greenhalgh, Umar Hussain, Tine Descamps, Sarah Nash, Mary Wilson, Roger Hunt, Cliona C Kirwan. The relationship between tumour associated macrophage markers and tumour, demographic & behavioural factors in 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 P5-04-27.
Abstract P5-06-20: Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer
Authors: Tajiri Wakako , Sugii Azusa , Ijichi Hideki , Ueo Hiroki , Koga Chinami , Nakamura Yoshiaki , Okamoto Masahiro , Taguchi Kennichi , Tokunaga Eriko
Published: March 2020

 The Clinical Treatment Score post-5 years (CTS5) is a prognostic tool to estimate the residual risk of distant recurrence (DR) after 5 years of endocrine therapy in postmenopausal women with estrogen receptor (ER)-positive breast cancer. (J Clin Oncol, 2018; 19: 1941-1947). CTS5 might be useful to decide the indication of extended adjuvant endocrine therapy after 5years.  This study was conducted to elucidate the usefulness of CTS5 for the prediction of late DR in postmenopausal women with ER-positive early breast cancer treated in our department.  CTS5 was calculated in 377 postmenopausal patients with ER-positive breast cancer who underwent surgery between 2003 and 2009. They had received 5-year adjuvant endocrine therapy without DR. CTS5 is stratified into three groups; low, intermediate and high risk of DR. The relationships between CTS5 and the clinicopathological characteristics and prognosis were evaluated.  According to CTS5, 202 (53.6%), 104 (27.6%) and 71 (18.8%) patients were divided into low, intermediate and high-risk of late DR groups. In the CTS5-high risk group, significantly more positive lymph nodes (p<0.0001), larger tumor size (p<0.0001), higher histological grade (p<0.0001), more administration of adjuvant chemotherapy (p<0.0001), more administration of adjuvant endocrine therapy of Aromatase inhibitor (AI) (p=0.0029), more visceral distant metastasis (p=0.0029), lower ER expression (p=0.0064) were observed. Significantly lower incidence of DR was observed in CTS5-low risk group. Thus, CTS5 was significantly prognostic for late DR. Intriguingly, in the CTS5-low risk group, administration of endocrine therapy of AI (p=0.0023), lower histological grade (HG1, 2; p=0.0011), ER high expression (TS; 6-8 p=0.0002), and positive PgR (p=0.0007) were significantly better DR-free survival (DRFS).  CTS5 demonstrated clinical validity for predicting late DR in this study cohort. IN the CTS5-low risk group, the incidence of late DR was significantly lower than that of in CTS5-intermediate or high risk group. The low CTS5 might be useful to decide the indication of 5-year adjuvant endocrine therapy in the postmenopausal patients with ER-positive early breast cancer.

Citation Format: Wakako Tajiri, Azusa Sugii, Hideki Ijichi, Hiroki Ueo, Chinami Koga, Yoshiaki Nakamura, Masahiro Okamoto, Kennichi Taguchi, Eriko Tokunaga. Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early 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 P5-06-20.
Abstract P5-06-24: Validation of the Johns Hopkins oncotype DX recurrence score estimator
Authors: Millado Kristen , Fogg Louis , Ghai Ritu , Cobleigh Melody
Published: March 2020

Objective

Oncotype DX (ODX) is a 21-gene assay used to predict the benefit of adjuvant chemotherapy in hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. However, the test is expensive and the incremental contribution of this assay to routinely available clinicopathological information and how to integrate that information to best inform clinical decision making is unknown. Several models have been developed to predict whether there are cases in which a clinician or patient could opt to forgo ODX because the outcome of the test might be predicted with a high degree of accuracy using routinely available measures. One such model was developed and validated at Johns Hopkins University. Here we used their recurrence score estimator to learn whether we could safely adopt the calculator for use at our institution to improve resource utilization.

Methods

An IRB-approved prospective database was created in 2010 for patients seen by a single medical oncologist at Rush University Medical Center and for whom oncotype DX was performed. From this database, patients were identified with HR+, HER2-negative, node-negative breast cancer and for whom age at diagnosis, tumor size, grade and Ki-67 were known. These data were entered into the Johns Hopkins breast cancer recurrence score estimator (http://www.breastrecurrenceestimator.onc.jhmi.edu). This model categorizes patients with a recurrence score (RS) of less than or equal to 25 as low risk and those with a score of greater than 25 as high risk.

Results

There were 189 patients. The mean age, tumor size, ER%, PR% and Ki-67% were 58 years old, 1.5 cm, 88%, 44% and 15% respectively. 14% had a RS greater than 25. The estimator assigned 65 patients to low risk, 59 of whom had a low RS and 6 with a high RS. The estimator assigned 4 patients to high risk, all of whom had a high RS.

Conclusions

The Johns Hopkins recurrence score estimator assigned 69 patients to low or high risk with 91.3% accuracy. Future analysis of a larger sample size is needed to optimize the accuracy of this estimator nationally. It may also be beneficial to separately analyze patients aged 50 or younger with an ODX score between 16 and 25 who had chemotherapy benefit in the TAILORx study in order to improve the utility of this risk estimator.

Citation Format: Kristen Millado, Louis Fogg, Ritu Ghai, Melody Cobleigh. Validation of the Johns Hopkins oncotype DX recurrence score estimator [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 P5-06-24.
Abstract P5-08-11: Applying risk-based follow-up strategies on the Dutch breast cancer population: Consequences for care and costs
Authors: Draeger Teresa , Voelkel Vinzenz , Groothuis-Oudshoorn Catharina GM , Lavric Miha , Veltman Jeroen , Dassen Anneriet , Boersma Lisbeth J. , Witteveen Annemieke , Sonke Gabe S. , Koffijberg Hendrik , Siesling Sabine
Published: March 2020

Purpose: An important aim of follow-up after primary breast cancer treatment is early detection of locoregional recurrences (LRR) to improve survival. This study proposes and simulates two personalized follow-up schemes based on LRR risk predictions provided by the INFLUENCE-nomogram (a time-dependent prognostic model for breast cancer-LRR) and quantifies their possible follow-up efficiency. Methods: Patients with early breast cancer who received surgery with curative intent between 2003 and 2008 were selected from the Netherlands Cancer Registry. The INFLUENCE-nomogram was used to estimate five annual LRR risks for every patient. Applying two thresholds, defined according to (a) Youden’s J-statistic, and (b) a pre-defined follow-up sensitivity of 95%, these risk estimations served as basis to decide when to schedule follow-up visits; thus, two personalized follow-up schemes were simulated. The number of potentially saved follow-up visits and corresponding cost savings for each follow-up scheme were compared to the current Dutch breast cancer guideline on a training and testing cohort. Results: Using LRR risk predictions for 30,379 Dutch breast cancer patients from 2003 to 2006 (training cohort), two thresholds were calculated. The threshold according to Youden’s approach yielded a follow-up sensitivity of 62.5% and a potential saving of 62.1% of follow-up visits and 24.8 M €. When the threshold corresponding to 95% follow-up sensitivity is used, 17.0% of follow-up visits and 7.0 M € could be saved. Similar results were obtained by applying these thresholds to the testing cohort of 11,462 patients from 2007 to 2008. Conclusion: Personalized follow-up schemes based on the INFLUENCE-nomogram’s individual risk estimations for breast cancer-LRR could decrease the number of follow-up visits if one accepts a limited risk of delayed LRR detection.

Citation Format: Teresa Draeger, Vinzenz Voelkel, Catharina GM Groothuis-Oudshoorn, Miha Lavric, Jeroen Veltman, Anneriet Dassen, Lisbeth J. Boersma, Annemieke Witteveen, Gabe S. Sonke, Hendrik Koffijberg, Sabine Siesling. Applying risk-based follow-up strategies on the Dutch breast cancer population: Consequences for care and costs [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 P5-08-11.
Abstract P5-11-03: Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors
Authors: Clifton Katherine Keaney , Raghavendra Akshara Singareeka , Yi Min , Litton Jennifer , Tripathy Debu , Karuturi Meghan
Published: March 2020

Background: CDK 4/6 inhibitors have become frontline treatment for patients (pts) with advanced hormone receptor (HR) positive breast cancer. There is limited data regarding post-progression outcomes in pts receiving CDK 4/6 inhibitors as standard of care. In this study, we analyzed treatment patterns and clinical outcomes of post-progression treatment in pts with advanced HR positive breast cancer after receiving CDK 4/6 inhibitors. Methods: Pts with metastatic breast cancer receiving CDK 4/6 inhibitors who received treatment after progression were identified from a cohort of pts at MDACC. Pts receiving CDK 4/6 inhibitors in a clinical trial were excluded. Clinical and demographic data as well as progression-free survival (PFS) was collected. Data was analyzed using Fischer's exact test for categorized variables and T test/Wilcoxon rank-sum test for continuous variables. PFS was analyzed using the Kaplan Meier method. Results: 206 pts who met eligibility criteria were included. Median age at metastatic diagnosis was 56 years-old and the majority of pts were white (n=160, 77.7%) with a pre- treatment performance status of 0 (n=168, 81.6%). The largest fraction of pts (n=98, 47.6%) received a chemotherapy agent following progression on a CDK 4/6 inhibitor while 19.4% (n=40) received endocrine therapy, 21.8% (n=45) received a biologic, 6.3% (N=13) received a different CDK 4/6 inhibitor and 4.9% (n=10) received an investigational therapy. The majority of pts who progressed on a subsequent agent had visceral progression (n=193, 93.7%). The median time to progression on an agent after CDK 4/6 inhibitor was 122 days. There was no statically significant difference in time to progression after CDK 4/6 inhibitor between pts receiving different classes of therapies, including CDK 4/6 inhibitors and investigational therapies (p=0.3). Conclusion: Pts in our cohort were more likely to receive chemotherapy following progression on a CDK 4/6 inhibitor. Reassuringly, there was no significant difference between time to progression on different agents. As CDK 4/6 inhibitors become frontline therapy for HR positive metastatic breast cancer, it is important to evaluate the sequencing of therapies as well as outcomes on subsequent agents.

Citation Format: Katherine Keaney Clifton, Akshara Singareeka Raghavendra, Min Yi, Jennifer Litton, Debu Tripathy, Meghan Karuturi. Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors [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 P5-11-03.
Abstract P5-11-16: The efficacy and safety of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC): A systematic review and meta-analysis
Authors: Jing Li , Fangmeng Fu , Liuwen Yu , Meng Huang , Yuxiang Lin , Qian Mei , Jinxing Lv , Chuan Wang
Published: March 2020

Background Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Surprisingly, the overall survival (OS) advantage of ribociclib was reported in the MONALEESE-7 trial. This study was conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+/HER2- ABC. MethodWe searched PUBMUD, MEDLINE, EMBASE et al to identify relevant randomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+/HER2- ABC. We extracted the hazard ratios (HRs) for progression-free survival (PFS) and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with random-effects model. Heterogeneity was assessed by I2 statistic. Result Eight trials and 4,580 patients were included in this meta-analysis. Both PFS (HR=0.54, 95% confidence interval [CI]: 0.50-0.59, p<0.00001) and OS (HR=0.79, 95% CI: 0.67-0.93, p=0.004) were significantly improved with CDK4/6 inhibitors for HR+/HER2- ABC. Similarly, the benefit was also manifested in ORR (RR=1.47, 95%CI: 1.30-1.67, p<0.00001) and CBR (RR=1.20, 95%CI: 1.12-1.30, p<0.00001). The improvement of PFS were observed in the combined treatment group, as both first-line (HR=0.56) and second-line therapy (HR=0.53), and irrespective of menopausal statue, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more toxicity profiles were observed with CDK4/6 inhibitors. The most common Grade 3-4 AEs is neutropenia (RR 31.95). Conclusion Substantial advantages of PFS and OS was observed for CDK4/6 inhibitors in HR+/HER2- ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increasing occurrence of AEs, most of which are reversable, manageable and acceptable. Therefore, CDK4/6 inhibitors could be recommended as the preferred options for HR+/HER2- ABC.

Citation Format: Li Jing, Fu Fangmeng, Yu Liuwen, Huang Meng, Lin Yuxiang, Mei Qian, Lv Jinxing, Wang Chuan. The efficacy and safety of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC): A systematic review and meta-analysis [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 P5-11-16.
Abstract P6-03-04: Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in breast cancer cells
Authors: Jokela Tiina A , Schones Dustin , LaBarge Mark A
Published: March 2020

Development of resistance to breast cancer (BC) therapy is frustratingly common. Multiple mechanisms of resistance have been identified including selection of genetic resistance, redundant signaling, and others. More recently, rare cancer cells were shown to be sporadically reprogrammed by the presence of anti-cancer drugs into transiently resistant states, then to expand later after cessation of therapy. We have demonstrated that the physical character and composition of tumor microenvironment (ME) components are determinants of BC cell drug resistance, however, the mechanism by which this phenomenon occurs is unclear. We hypothesize that epigenetic reprogramming is not rare or sporadic, indeed, that specific tumor ME components impose epigenetic states that beget the expression of gene clusters that put cancer cells into drug-tolerant states. Our current pharmacopeia targets cancer cells, not their ME. Some tumor ME components, e.g. extracellular matrices (ECM), have half-lives that span years, and growth factors with typically short half-lives can be stabilized by direct association with ECM. Thus, a ME-imposed drug tolerance mechanism would explain how resistance can arise rapidly, in multiple locations, without the need for genetic selection. Because ME-cell interactions lead to activation of specific pathways, based on canonical receptor-ligand models, we should be able to circumvent ME-imposed drug tolerance by addition of molecules that alter ME-induced signaling. Clusters of genes that are activated in multidrug resistant breast cancer cells identified potential markers of drug tolerance. ME-drivers of the drug tolerance markers were identified in high-throughput cell-based screens with the MicroEnvironment MicroArray (MEMA) platform. BC cells were exposed in parallel to over 1000 unique combinatorial MEs, which were chosen to mimic normal mammary gland, and luminal or basal BC tumor MEs. Single-cell resolution analysis revealed MEs that induce and maintain drug-tolerance markers. Longer-term functional experiments validated that the identified MEs also increased BC cells drug tolerance. Chromatin accessibility profiling with ATAC-sequencing demonstrated that BC cells cultured in those drug-tolerance inducing MEs exhibit chromatin opening in promoter regions of genes linked to epithelial plasticity (e.g. Axl, SNAI2, Vimentin, TWIST1) within 24h of exposure. These results support the concept that specific MEs drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.

Citation Format: Tiina A Jokela, Dustin Schones, Mark A LaBarge. Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in 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 P6-03-04.