bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental regulation of the intestinal FGF19 system in domestic pigs
Authors: Gavaldà-Navarro Aleix , Pastor Jose J. , Mereu Alessandro , Villarroya Francesc , Ipharraguerre Ignacio R.
Published: February 2018

Fibroblast growth factor-19 (FGF19) is an emerging endocrine factor involved in the regulation of bile acid homeostasis and energy metabolism in rodents and humans. In pigs, however, the FGF19 system remains largely unexplored. This study was designed to investigate the developmental regulation of the FGF19 system in domestic pigs. Samples of intestinal sections, liver, and plasma were collected from 24 pigs ( n = 6) at four developmental stages (birth, preweaning, postweaning, and adulthood). In the intestine, expression of the farnesoid X receptor (FXR) and FGF19 showed a congruent time- and region-dependent regulation, beginning soon after birth to achieve maximal expression in ileum during adulthood. The same temporal pattern was followed by the circulating concentration of FGF19, and these changes were accompanied by a time-related increase in the ileal proportion of bile acids that potently activate FXR. Conversely, genes belonging to the FGF19 signaling machinery achieved maximal expression in the small intestine at birth to decrease sharply afterward. In the liver, gene expression of FGF19 receptors and enzymes involved in bile acid biosynthesis paralleled after-birth changes in plasma concentration of this enterokine and attained a maximum during postweaning when plasma FGF19 was the lowest. Although detectable at birth, the hepatic expression of genes belonging to the bile acid-FXR-FGF19 pathway was low before the onset of enteral feeding. In summary, the porcine FGF19 system is present from birth, operative before the onset of enteral feeding, and regulated in a temporal and section-specific manner.

NEW & NOTEWORTHY Fibroblast growth factor-19 (FGF19) is an emerging endocrine factor. The domestic pig is a translational model of value in biomedical research. We show for the first time that in pigs the intestinal FGF19 system is present from birth, operative before the onset of enteral feeding, and regulated in a temporal and section-specific manner. This work identifies pigs as a suitable model for investigating the implications of FGF19 signaling within and beyond the gut-liver axis.
Traffic Peak Period Detection from an Image Processing View
Authors: Xiao Jianli , Li Hang , Wang Xiang , Yuan Shangcao
Published: February 2018

Traffic peak period detection is very important for the guidance and control of traffic flow. Most common methods for traffic peak period detection are based on data analysis. They have achieved good performance. However, the detection processes are not intuitional enough. Besides that, the accuracy of these methods needs to be improved further. From an image processing view, we introduce a concept in corner detection, sharpness, to detect the traffic peak periods in this paper. The proposed method takes the traffic peak period detection problem as a salient point detection problem and uses the image processing strategies to solve this problem. Firstly, it generates a speed curve image with the speed data. With this image, the method for detection of salient points is adopted to obtain the peak point candidates. If one candidate has the lowest speed value, this candidate is the peak point. Finally, the peak period is gotten by moving forward and backward the corresponding time of the peak point with a time interval. Experimental results show that the proposed method has achieved higher accuracy. More importantly, as the proposed method solves the traffic peak period detection problem from an image processing view, it has more intuition.
Transvaginal Small Bowel Evisceration following Abdominoperineal Resection
Authors: Kunduz Enver , Bektasoglu Huseyin , Yigman Samet , Akbulut Huseyin
Published: February 2018

Abdominoperineal resection (APR) is one of the surgical techniques performed for the distal rectal cancer. The perineal herniation is one of the complications of APR surgery. In this report, we aim to demonstrate a rare case of small bowel evisceration and strangulation secondary to the transvaginal herniation evolved in the late stage after perineal hernia repair following laparoscopic APR.
Boundedness and Asymptotic Stability for the Solution of Homogeneous Volterra Discrete Equations
Authors: Messina E. , Vecchio A.
Published: February 2018

We consider homogeneous linear Volterra Discrete Equations and we study the asymptotic behaviour of their solutions under hypothesis on the sign of the coefficients and of the first- and second-order differences. The results are then used to analyse the numerical stability of some classes of Volterra integrodifferential equations.
Percutaneous Ethanol Injection in Combination with Laser Ablation for a 100 ml Partially Cystic Thyroid Nodule
Authors: Negro Roberto , Greco Gabriele
Published: February 2018

Until nonsurgical techniques like laser ablation (LA) or radiofrequency became available, patients suffering from large nodules with compressive symptoms were addressed to surgery. We describe the case of a 59-year-old woman with a large, partially cystic thyroid nodule having a volume of about 100 ml. As the patient refused surgery, despite her constant local discomfort, such large partially cystic nodule underwent several percutaneous ethanol injections (PEI) and then was submitted to LA. The combination of these two procedures allowed firstly complete disappearance of the cystic component and secondly a significant reduction of thyroid nodule, which finally measured 17 ml in volume (82% reduction compared to baseline). This case demonstrates that even in very large partially cystic nodules LA preceded by PEI represents a valid alternative to surgery.
Prevalence of Intestinal Parasites and Associated Factors among Pulmonary Tuberculosis Suspected Patients Attending University of Gondar Hospital, Gondar, Northwest Ethiopia
Authors: Tegegne Yalewayker , Wondmagegn Tadelo , Worku Ligabaw , Jejaw Zeleke Ayalew
Published: February 2018

Introduction. Intestinal parasitic infections are among the major public health problems in developing countries. Hence, it is significant to explore coinfection with intestinal parasites and pulmonary tuberculosis because coinfection increases the complexity of control and prevention of pulmonary tuberculosis and parasitic diseases.Objective. To assess the prevalence of intestinal parasites among pulmonary tuberculosis suspected patients.Method. Institutional based cross-sectional study was conducted at University of Gondar Hospital from March to May, 2017. Stool samples were taken from each participant and examined by direct microscopy and concentration technique. Descriptive statistics was performed and chi-square test was used to show the association between variables.Pvalues of <0.05 were considered statistically significant.Results. Intestinal parasites were detected in 50 (19.6%) among a total of 256 pulmonary tuberculosis suspected patients who were included in the study, whereas the prevalence of pulmonary tuberculosis was 16.8% (43/256). Pulmonary tuberculosis and intestinal parasite coinfection was detected in 5 (2.0%) of the participants. The most prevalent intestinal parasites infection in this study wasAscaris lumbricoides,15 (5.85%), followed byEntamoeba histolytica/dispar,14 (5.46%), and Hookworm, 13 (5.1%).Conclusion. The prevalence of intestinal parasites and their coinfection rate with pulmonary tuberculosis among pulmonary tuberculosis suspected patients were considerable.
Abstract BS2-2: The perivascular niche protects dormant disseminated tumor cells from therapy
Authors: Ghajar CM
Published: February 2018

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumor biology. To address these questions, we use metastasis assays in mice and zebrafish and have determined that the perivascular niche of distant sites like the lung, bone marrow and brain regulate DTC dormancy. We have developed organotypic microvascular niches to specify that endothelial cells regulate breast cancer cell growth, and applied proteomics to identify endothelial-derived mediators of DTC dormancy. More recently, we have begun to explore whether the perivascular niche confers therapeutic resistance to DTCs. I will present data that suggests strongly that the perivascular niche regulates therapeutic resistance of DTCs in a manner that is independent from its role in regulating DTC growth. We have uncovered mediators of perivascular signaling that, when targeted, cause dormant DTCs to respond robustly to chemotherapy. Critically, inhibiting these mediators causes chemosensitization without inducing dormant DTCs to re-enter the cell cycle. We are currently testing this treatment paradigm in pre-clinical models to determine the efficacy in killing dormant DTCs through this approach. I will discuss pre-clinical trial design and important caveats to accurately gauging whether eradication of dormant DTCs significantly prolongs metastasis-free survival.

Citation Format: Ghajar CM. The perivascular niche protects dormant disseminated tumor cells from therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS2-2.
Abstract CS1-2: Searching for the optimal duration of adjuvant endocrine therapy in breast cancer
Authors: Stearns V
Published: February 2018

Endocrine therapy is an integral part of the adjuvant systemic management of women with early stage hormone receptor-positive breast cancer. Adjuvant endocrine therpay is associated with significant improvements in disease-free and overall survival. Several adjuvant endocrine therapy approaches are available to women based on their menopausal status, disease stage, tumor characteristics, co-morbidities, and individual preferences. The optimal duration of adjuvant endocrine therapy established to date is 5 to 10 years.

Extended adjuvant endocrine therpay provides only a modest additional benefit compared to a 5-year treatment duration. Studies reported in recent years offer some guidance to help clinicians provide recommendations regarding the type and duration of adjuvant endocrine therpay. Clinicians must weigh treatment benefits and potential adverse events for individual patients. Models to help individualize treatment recommendations are needed. Several opportunities are available to predict personalized risk of recurrence and likelihood of developing bothersome symptoms or serious adverse events. Women should have a close follow up with their physicians during the first year or therapy to identify emerging symptoms and to provide early interventions to optimize adherence to adjuvant endocrine therpay. Clinicians should engage in continuous discussion with each woman regarding the duration of treatment most appropriate for her and revisit recommendations based on evolving clinical trial results or events in the patient's life.

In this presentation I will discuss the available data regarding optimal length of adjuvant endocrine therapy. I will review expected benefits and toxicities. I will also discuss emerging biomarkers and approaches that may help individualize treatment duration for women with hormone receptor-positive breast cancer.

Citation Format: Stearns V. Searching for the optimal duration of adjuvant endocrine therapy in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr CS1-2.
Abstract ES10-2: A novel human derived organoid platform for breast cancer research
Authors: Kopper O
Published: February 2018

Breast cancer (BC) is a heterogeneous disease consisting of multiple tumor subtypes. We have recently established a novel human derived 3D in-vitro platform, which enables long-term expansion of BC organoids. Thus, we were able to derive ∼100 BC organoid lines from both primary and metastatic tumors. These lines represent the diversity of the disease and faithfully recapitulate the histology, hormone receptor and HER2 status of the tumors from which they were derived. Whole genome sequencing analysis of tumor-organoid pairs, demonstrated that copy number alterations and single nucleotide variations, were broadly maintained, even after extended passaging. BC organoids allowed performing in-vitro drug screens that were consistent with in-vivo xenografts and patient response.

Thus, we suggest that this platform can be utilized as a valuable tool for BC research, facilitate drug development and present us with new opportunities for personalized medicine.

Citation Format: Kopper O. A novel human derived organoid platform for breast cancer research [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES10-2.
Abstract ES11-1: Luminal ABC: optimal use of all available options?
Authors: DeMichele AM
Published: February 2018

Despite advanced in early detection and aggressive adjuvant endocrine therapy, recurrence and metastasis of estrogen-receptor (ER)- positive breast cancer remains a problem, with a substantial proportion of patients relapsing years after diagnosis. Biologically, these tumors are primarily of the luminal subtype, amenable to anti-estrogen strategies that can control disease growth and limit metastatic spread. However, resistance and progression are universal, and patients will eventually stop responding to endocrine approaches. Advances in our understanding of luminal breast cancer biology, metastatic progression and endocrine resistance have led to new approaches and additional targets for intervention. Most important among these are interactions between ER signaling pathways and cell cycle control mechanisms or PI3K/mTor signaling, leading to new strategies incorporating cyclin-dependent kinase (cdk) and mTOR inhibitors, respectively, into endocrine therapy. While successful, many questions remain unanswered regarding optimal combinations and sequencing of these agents in specific populations, and management at the time of progression. This session will address (1) the evidence supporting the use of cdk 4/6 and mTOR inhibitors in standard practice for luminal advanced breast cancer, including agent selection and management of toxicity, (2) current understanding of resistance mechanisms and (3) next generation clinical trials designed to address resistance and improve outcomes in women with luminal advanced breast cancer.

Citation Format: DeMichele AM. Luminal ABC: optimal use of all available options? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES11-1.
Abstract ES5-3: Biologic and health system determinants of breast cancer disparities in African Americans
Authors: Reeder-Hayes KE
Published: February 2018

Despite significant progress in breast cancer screening and treatment over three decades, racial disparities in breast cancer mortality between African American (AA) and White women continue to widen. A cascade of factors, both biological and ecological, drive these disparities, including: (1) differences in presenting stage and uptake of breast cancer screening; (2) differences in subtype distribution, beginning with over-representation of hormone receptor negative, HER2 negative (triple negative) tumors in young AA women, and extending to recent evidence of potential biologic differences within hormone receptor positive (HR+) subtypes; (3) barriers to appropriate delivery of breast cancer care for AA women, including chemotherapy, radiation and targeted endocrine and biologic therapies; (4) differences in the impact of cancer treatment during survivorship and the impact of co-morbidities on post-diagnosis risk, including obesity, health-related quality of life and financial toxicity. Although the biologic and health system contributors to breast cancer disparities in AA women have been well studied, interventions designed to improve health equity for AA women with breast cancer are only beginning to emerge. Meaningful improvement in the survival gap will require close examination of how biology and healthcare access act as drivers of sub-optimal outcomes, and how both can be targeted to improve outcomes. Interventions with promise to impact racial disparities include programs that improve access to screening, patient navigation programs, and interventions to improve adherence to endocrine therapy, and some of these approaches are being tested in ongoing clinical trials. The impact of access to insurance should also be considered as an intervention for vulnerable populations, including AA women. Basic and translational research including efforts to identify therapeutic targets in triple negative breast cancer subtypes and to leverage genomics for better identification of high risk HR+ cancers may also disproportionately benefit AA patients due to their over-representation in these subtypes, but these efforts depend on adequate representation of AA patients in tissue biobanks and clinical trials, as well as adequate access to genomic testing.

Citation Format: Reeder-Hayes KE. Biologic and health system determinants of breast cancer disparities in African Americans [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES5-3.
Abstract ES6-3: Opportunities for immune therapy and prevention
Authors: Vonderheide RH
Published: February 2018

The recent demonstration of modest single-agent activity of PD-L1 and PD-1 antibodies in patients with breast cancer has generated hope for advancing immunotherapy in this disease. Depending on the subtype of breast cancer, in both primary and metastatic disease, the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to non-immune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neo-epitopes – factors linked to response to checkpoint blockade in other malignancies – are all relatively modest in breast cancer, compared to melanoma or lung cancer. Thus, in breast cancer, combinations of immune agents with non-redundant mechanisms of action are the high-priority strategies. For most breast cancers that exhibit relatively modest T cell infiltration, major challenges include immune suppression in the tumor microenvironment as well as failed or suboptimal T cell priming. Agents that trigger de novo T cell responses may be critical for successful development of cancer immunotherapy and immune prevention in breast cancer. Success may also require reaching beyond nonsynonymous mutations as the T cell epitopes to target, especially as numerous unmutated proteins were validated as breast cancer associated antigens in the pre-checkpoint era. A deeper understanding of the immunobiology of breast cancer will be critical for immunotherapy to become broadly relevant in this disease.

Citation Format: Vonderheide RH. Opportunities for immune therapy and prevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES6-3.
Abstract ES7-1: Challenges in the management of locoregional recurrence
Authors: Morrow M
Published: February 2018

The increasing trend toward tailoring treatment of the primary breast cancer with limited surgery of both the breast and axilla has increased the challenge of managing locoregional recurrence (LRR). In the era when patients uniformly had axillary dissection, the appropriateness of repeat sentinel node biopsy was not a question. Similarly, the dogma that all ipsilateral breast tumor recurrences must be treated with mastectomy if the breast has been previously irradiated is also being challenged. LRR events are infrequent with modern multi-modality therapy, and there are no randomized trials to address these questions.

Re-operative sentinel node (SN) biopsy after breast conserving surgery therapy (BCT) has been shown to be feasible, with the likelihood of identifying additional SNs related to the number of nodes excised at the time of initial SN biopsy. The accuracy of SN biopsy after mastectomy is less clear. However, the impact of identification of nodal disease on management of LRR is controversial. In a study of 12 patients with isolated chest wall recurrence post mastectomy, 10/12 had successful mapping and 7/10 had an axillary SN. The absence of nodal metastases was an indication to avoid supraclavicular RT (Johnson J. Ann Surg Oncol 2016;23:715). In a study of 83 patients with in breast (n=79) or chest wall recurrence who were clinically node negative, 47 had axillary surgery and 36 did not. At a median of 4.2 years after LR, rates of axillary and non-axillary local recurrence, distant metastases, and death did not differ significantly between groups (Ugras S. Ann Surg Oncol 2016). With the findings of the CALOR trial that systemic chemotherapy is beneficial in the management of LRR, the finding of axillary metastases is less likely to influence systemic therapy than in the past and repeat axillary staging could potentially be avoided.

In the untreated breast, drainage to the contralateral axilla is very rare and contralateral axillary metastases classify a patient as Stage IV. After initial axillary dissection, between 4% and 33% of patients with local recurrence will have contralateral axillary drainage. In a systemic review of 48 cases of contralateral nodal recurrence without other distant metastatic disease, at a mean follow-up of 50.3 months disease free survival was 65% and overall survival 83% after treatment that included both local and systemic therapy (Moossdorff M. Eur J Surg Oncol 2015;41:1128). These findings raise the possibility that in the setting of LR, contralateral axillary metastases should be treated aggressively for cure after excluding distant metastases.

Citation Format: Morrow M. Challenges in the management of locoregional recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES7-1.
Abstract ES7-2: Local regional recurrence
Authors: Zellars RC
Published: February 2018

Through careful study, we are certain of the management necessary to achieve excellent local regional control rates in early stage breast cancer (ESBC). Due to less study, there is some uncertainty on how to best manage the small percentage of women with ESBC who have local regional recurrences (LRR). Classically, the management of LRR requires some form of salvage surgery. The surgery could be limited, as in wide local excision after initial mastectomy, or more radical, as in mastectomy after initial breast conserving therapy. Often after salvage surgery, radiation, or in some cases re-irradiation, is added. Today there is information which calls into question whether these common treatments for LRR are required, sufficient or the sole options. During this session, we will review the data supporting these common treatments for LRR, as well as alternatives such as surgery alone, partial breast re-irradiation, photodynamic therapy and hyperthermia. After the presentation, the attendee will have a greater understanding of the various local therapy options for treating LRR of breast cancer and the need for prospective study of this small but significant group of patients.

Citation Format: Zellars RC. Local regional recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES7-2.
Abstract ES8-2: Exosome analysis in breast cancer: Clinical translation
Authors: Bromberg JF
Published: February 2018

There is a growing appreciation that tumor secreted factors can function by orchestrating the cross-talk between cancer, stromal and immune cells. Tumors constitutively release membrane-derived extracellular vesicles (EVs) or exosomes that are readily detected in body fluids and have been appreciated to play important roles in signaling, immunomodulation and metastasis. We examined the role of circulating and stromal-derived EVs in hormonal therapy resistant breast cancer. We identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal-therapy resistant metastatic breast cancer. We generated xenograft models of hormonal therapy-resistant (HTR) metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HT-resistant cells had acquired host-derived (murine) mtDNA promoting ER-independent metabolic proficiency. Functional studies identified cancer associated fibroblasts (CAF)-derived EVs (from patients and xenograft models) laden with the complete mitochondrial genome as a mediator of this phenotype. Specifically, the treatment of HT-naïve cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV-mtDNA especially in cancer stem-like cells, expression of EV-mtRNA and restoration of metabolic activity. In addition to mtDNA, we also identified miR-221 in CAF derived EVs as a driver of HTR disease. Specifically, EV-mediated transfer of miR-221 to cancer cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi cancer stem like cells. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF EVs. Our results illuminate how EV-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control.

Citation Format: Bromberg JF. Exosome analysis in breast cancer: Clinical translation [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES8-2.
Abstract ES9-3: Androgen, progesterone and glucocorticoid receptors: Drivers of breast tumor progression or reprogramming of steroid receptors during breast tumor progression
Authors: Conzen SD
Published: February 2018

In normal physiology, glucocorticoid receptor (GR) activity regulates thousand of genes whose products modulate metabolism, inflammation, cell cycle and apoptosis/cell survival pathways. Synthetic GR agonists, or glucocorticoids (GCs), are often used to treat hematologic malignancies because of GR's ability to induce proapoptotic gene expression, inhibit nuclear factor – κB, and induce cell cycle arrest. In contrast, recent examination of GR expression and activity in human breast cancer models and clinical specimens has suggested that GR expression has remarkably diverse roles in breast cancer subtypes. In ER+ breast cancer, GR appears to modulate ER-regulated transcriptional activity through ER/GR receptor crosstalk resulting in antagonism of ER-associated proliferation. However, in ER-negative breast cancer (including TNBC), high tumor GR expression is associated with poor prognosis, anti-apoptotic signaling, and chemotherapy resistance. In addition, high GR activity in the tumor microenvironment is predicted to be immunosuppressive. Recently described selective GR modulators are expected to help dissect divergent GR mechanisms present in breast cancer subtypes.

Citation Format: Conzen SD. Androgen, progesterone and glucocorticoid receptors: Drivers of breast tumor progression or reprogramming of steroid receptors during breast tumor progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES9-3.
Abstract MS2-2: Understanding the unique biology of ILC
Authors: Oesterreich S
Published: February 2018

Invasive lobular breast cancer (ILC) is characterized by distinct etiological, pathological, and clinical features, yet the underlying biology is poorly understood. To extend the molecular determinants of ILC beyond the well-known loss of E-cadherin, we combined a plethora of in silico and wet-bench approaches, and comprehensively characterized ILC tumor models and clinical samples.

In support of recent data from The Cancer Genome Atlas on differences in mutations in critical ER co-factors between invasive lobular and ductal cancers, we have identified distinct ER signaling pathways, and mechanisms of endocrine resistance in ILC. These include the acquisition of unique ER target genes, activation of IGF and FGFR signaling, and changes in metabolic pathways. As part of our efforts to elucidate mediators of ILC progression, transcriptomic analysis of primary tissue from patients with and without disease recurrence identified potential genetic drivers, including Cortactin, an actin binding protein with a known role in metastasis. To further identify genes that mediate the unique metastatic properties of ILC cells, we sequenced metastases to the ovary and the gastrointestinal tract, and uncovered pathways that might serve as critical vulnerabilities and therapeutic opportunities. In this lecture, I will review our progress, and discuss the potential clinical significance and implications of these findings.

Citation Format: Oesterreich S. Understanding the unique biology of ILC [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr MS2-2.
Abstract OI-1: Tackling Breast Cancer Diversity
Authors: Turner NC
Published: February 2018

Breast cancer is a highly diverse disease with multiple subtypes and driver mutations. Further diversity may develop, particularly in metastatic breast cancer, due to the selective pressure of treatment. In ER positive breast cancer, activating mutations of the oestrogen receptor (ESR1), along with mutations in the NF1, KRAS and FGFR genes, are all enriched in endocrine resistant breast cancer, although rare in untreated primary breast cancer.

This diversity presents a substantial challenge to the treatment of metastatic breast cancer, with new therapeutic approaches required to tackle this heterogeneity. Circulating tumour DNA analysis, to identify selected mutations in the tumour and guide matching targeted therapy, has preliminary evidence of clinical utility. Targeting common phenotypes presents an alterative therapeutic approach, targeting the dependence of luminal breast cancer on CDK4/6 to initiate cell cycle entry. Pre-clinical evidence supports combining CDK4/6 inhibition with mutation-targeted therapies, although implementing these combinations presents a substantial clinical translational challenge.

A novel approach to overcoming tumour heterogeneity is to identify and target micro-metastatic cancer in the adjuvant setting. Micro-metastatic cancer can be detected with highly sensitive circulating tumour DNA analysis for minimal residual disease (MRD) detection. This may open up a new paradigm of treatment guided by MRD monitoring, potentially treating cancer in a setting where the cancer may be less genetically diverse, with lower potential to develop resistance to therapy.

Citation Format: Turner NC. Tackling Breast Cancer Diversity [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OI-1.
Abstract OT2-01-05: Sentinel lymphnode biopsy (SLNB) and targeted axillary surgery (TAS) by indocyaningreen (ICG) and a novel near-infrared color camera system - a prospectively randomised, multicenter study to avoid radioactivity in a time-/cost-saving procedure in primary breast cancer
Authors: Kern P , Kimmig R , Rezai M , Hoffmann O , Bücker I , Braun M
Published: February 2018

Background: Sentinel lymph node biopsy (SLNB) by radioactively labelled 99mTechnetium +/- patent blue is so far the current standard in SLN detection. However, it remains a time- and cost-consuming procedure requiring the availability of a nuclear medicine department and a precise coordination with the subsequent surgery. It could be desirable to empower surgeons to be independent from availability of a nuclear source and to spare patients from radioactivity. Indocyanine green (ICG) as a fluorescent coloring agent is already known as safe in diagnostics for heart, circulation, liver and eye disease and may represent a valid alternative to 99mTc and patent blue (PBD), especially as it does not cause aesthetic impairment of the breast, with ICG being only visible with near infra-red light.

Methods: This prospective, randomized study is a non-inferiority trial to evaluate ICG-fluorescence as an alternative to either 99mTc and/or patent blue dye for sentinel lymph node detection of primary breast cancer with and without neoadjuvant chemotherapy.

Patients, aged 18 - 80 years, with unilateral or bilateral, unifocal or multifocal/ multicentric primary breast cancer without signs of metastases and written consent are eligible for this study. ECOG status of 0-2 and life expectancy > 1 year is required. All BMI classes are admitted to the study, with predefined subgroups of a) <= 20 b) >20-30 c) >30-40 d) >40. Tumor stages included are a) Tis (>= 4 cm) b) T1 c) T2 and d) T3. ICG-guided SLNB may be applied in patients in the following settings: a) before neoadjuvant, b) after neoadjuvant chemotherapy.

Primary Endpoints: Rate of SLN detection by either of the methods in the following 3 arms of the trial:

Arm A: 99mTc + patent blue dye (PBD)

Arm B: 99mTc + indocyanine green (ICG)

Arm C: Indocyanine green (ICG)

Secondary Endpoints:

- Time to identify (TTI) sentinel lymph node(s) (min)

- Number of sentinel lymph nodes (SLN) and non-sentinel lymph nodes (non-SLN)

- Rate of concordance of detection by 99mTc+patent blue dye (PBD) vs. 99mTc + ICG

- Dose of radioactivity omitted in Arm C vs. Arm A & B

Results: This trial is in progress.

Citation Format: Kern P, Kimmig R, Rezai M, Hoffmann O, Bücker I, Braun M. Sentinel lymphnode biopsy (SLNB) and targeted axillary surgery (TAS) by indocyaningreen (ICG) and a novel near-infrared color camera system - a prospectively randomised, multicenter study to avoid radioactivity in a time-/cost-saving procedure in primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-01-05.
Abstract OT2-07-01: Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative breast cancer
Authors: Soliman HH , Hogue D , Han H , Lee C , Ismail-Khan R , Khong H , Niell B , Czerniecki B
Published: February 2018

Background: The host anti-tumor immune response plays an important role in determining natural history and therapy response for early stage breast cancer. Tumors with high levels of lymphocytic infiltration appear to have a superior prognosis and response rate to neoadjuvant chemotherapy. However, these tumors are in the minority so methods to enhance tumor lymphocyte infiltration should be identified. The oncolytic virus, talimogene laherparpvec (TVEC) is a genetically modified HSV1 virus which selectively replicates in transformed cells while sparing normal tissue. This leads to lysis of infected tumor cells along with co-expression of GM-CSF to elicit an enhanced anti-tumor immune response. Prior data has shown TVEC can be safely combined with chemotherapy in other indications, so we launched an investigator initiated study to determine the safety and efficacy of combining TVEC with neoadjuvant dose dense chemotherapy in stage II-III TNBC.

Study design: The study is a phase 1 (2 dose levels of TVEC, 3+3 design) and phase 2 single arm Simon two stage combination trial. Primary endpoints of phase 1 is safety of intratumoral TVEC (DL1=106 PFU x 5 injections, DL2=106 PFU x 1 then 108 PFU x 4 injections) administered q2-3 weeks concurrently with weekly paclitaxel followed by standard dose dense AC x 4 and local therapy as indicated. Phase 2 primary endpoint is pCR rate of the study treatment, secondary endpoints include DFS, OS, immune correlates in resected tumor specimens. Eligibility criteria includes females >17 years old, newly diagnosed T2-3N0-3 TNBC, adequate organ function, primary tumor amenable to injection with TVEC, no immunosuppressive or autoimmune conditions, no inflammatory or bilateral/multifocal disease. Sample size is up to 49 patients (12 phase 1, 37 phase 2) with 80% power to detect increase in pCR rate from 30% to 50% with one sided p=.1 in phase 2.

Study status: This novel Amgen supported investigator initiated study activated to accrual 3/2017 and first patient on study was on 5/2017. The study is currently open only at the Moffitt Cancer Center. Target study completion date 8/2021. (NCT02779855)

Citation Format: Soliman HH, Hogue D, Han H, Lee C, Ismail-Khan R, Khong H, Niell B, Czerniecki B. Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-01.
Abstract OT3-05-11: Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic breast cancer
Authors: Mayer EL , Wander SA , Regan MM , DeMichele AM , Forero A , Rimawi MF , Ma CX , Cristofanilli M , Anders CK , Huang Bartlett C , Koehler M , Winer EP , Burstein HJ
Published: February 2018

Background:

CDK4/6 inhibition (CDK4/6i) has a significant role in contemporary management of hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The addition of a CDK4/6i to endocrine therapy (ET) in HR+/HER2- MBC leads to prolongation of progression-free survival in previously untreated and pre-treated HR+/HER2- MBC. Mechanisms of resistance to CDK4/6i are not well described, and it is not known if continuation of CDK4/6i with subsequent lines of ET improves outcomes over ET alone. Further, preclinical data suggest combination therapy with ET, CDK4/6i, and anti-PDL1 may provide synergistic efficacy. The PACE trial was designed to determine the optimal subsequent line of therapy in patients (pts) with HR+ /HER2- MBC that has progressed despite prior CDK4/6 inhibition and endocrine therapy.

Methods:

PACE (NCT03147287) is a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for Palbociclib (P) monotherapy crossover at time of progression); Arm B: fulvestrant + P; or Arm C: fulvestrant + P + avelumab. The primary objective is to evaluate progression-free survival (PFS) with the combination of fulvestrant + P vs. fulvestrant alone; secondary objectives include overall response (OR), safety and tolerability, and PFS comparisons of avelumab containing arm vs other arms. Exploratory objectives include assessment of outcomes in predefined molecular subgroups (i.e. ESR mutation, PI3K mutation, and loss of Rb); and comparing OR by RECIST vs irRECIST in the avelumab cohort. Extensive molecular profiling of tissue, ctDNA, and CTCs for markers of response and resistance to therapy is also planned. Eligible pts have HR+/HER2- MBC, with prior response to and subsequent progression on any CDK4/6i and ET, defined as at least 6 months of prior treatment, with confirmed subsequent progression, and no more than one prior P dose reduction for toxicity. Pts may have had 1-2 prior ET (aromatase inhibitor or tamoxifen), and 0-1 prior lines of chemotherapy. A sample size of 220 patients is planned.

Citation Format: Mayer EL, Wander SA, Regan MM, DeMichele AM, Forero A, Rimawi MF, Ma CX, Cristofanilli M, Anders CK, Huang Bartlett C, Koehler M, Winer EP, Burstein HJ. Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-11.
Abstract P1-01-15: Investigation of phosphoserine aminotransferase 1 and its role in breast cancer progression
Authors: Metcalf S , Kruer T , Klinge C , Clem B
Published: February 2018

Metastasis and endocrine resistance are two factors that complicate therapeutic intervention in breast cancer patients and lead to poorer overall survival. Metastasis is known to be responsible for 90% of cancer related deaths, and is especially prevalent in triple negative breast cancer (TNBC); while endocrine resistance can affect up to 50% of patients diagnosed with estrogen receptor positive breast cancer (ER+BC). Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second step within de novo serine biosynthesis and increased expression of enzymes in this pathway have been linked to progression of breast cancer and poor clinical outcomes. Within our preliminary retrospective analysis of human breast cancer patients, we identified an inverse association with elevated transcript levels and poorer distant metastasis free survival, which, coupled to a previously reported correlation of PSAT1 with response to endocrine therapy in patients with ER+BC, we postulate that PSAT1 contributes to breast cancer progression through promotion of metastasis and/or endocrine resistance. To initially determine relevance for PSAT1, immunohistochemistry was performed to determine PSAT1 expression in human breast cancer patients. We found that PSAT1 expression is increased through breast cancer progression, with highest levels observed within metastatic conditions. To investigate the metastatic contribution of PSAT1, we silenced PSAT1 expression within the triple negative breast cancer cell line (TNBC), MDA-MB-231. While suppression of PSAT1 had no effect on proliferation, there was a significant decrease in the motility and invasion of these cells. In addition, decreased PSAT1 substantially inhibited lung metastasis following tail-vein injections of MDA-MB-231 cells in vivo. To investigate PSAT1's role in endocrine resistance, we used parental MCF-7 cells and an endocrine-resistant derivative cell line (LY2) and found that LY2-resistant cells exhibited higher PSAT1 expression compared to parental MCF-7 cells. Lastly, suppression of PSAT1 was able to sensitize the LY2 cells to 4-hydroxytamoxifen treatment. Taken together, these data indicate that PSAT1 may contribute to the progression of human breast cancer via either metastasis or endocrine resistance or both and could potentially serve as a viable target for new therapies.

Citation Format: Metcalf S, Kruer T, Klinge C, Clem B. Investigation of phosphoserine aminotransferase 1 and its role in breast cancer progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-15.
Abstract P1-01-16: Detection of disseminated tumor cells in DCIS patients impacts local recurrence
Authors: Walter VP , Taran F-A , Wallwiener M , Brucker SY , Hartkopf AD
Published: February 2018

Background

Recently it was shown that tumor cell dissemination is an early event in breast cancer progression (Hosseini et al., Nature 2016). This has been backed up by an assessment of over 100,000 patients with in situ carcinoma (DCIS), where some patients developed distant metastases and died from breast cancer without presenting with local invasive recurrence (Narod et al., JAMA Oncology 2015). We therefore analyzed the presence and clinical impact of disseminated tumor cells (DTC) in the bone marrow (BM) of DCIS patients.

Methods

BM aspirates were collected from patients undergoing surgery for primary DCIS at Tuebingen University Hospital between 2001 and 2016. Exclusion criteria were presence of invasive breast cancer, bilateral or metastatic disease as well as other malignancies in their history. DTC were identified by immunocytochemistry using the A45-B/B3 anti-pancytokeratin antibody.

Results

627 patients were included. Median follow-up was 49 months. 72 (11%) had detectable DTC. The detection of DTC was not significantly associated with lymph node positivity (3/479, Fisher's exact test: p=0.307) or tumor size (median 30mm, Wilcoxon test: p=0.952).

In 33 (5%) women, a disease recurrence was observed. Of 31 local recurrences 19 were invasive. 7 Patients developed distant metastases, four without an invasive recurrence beforehand. 14 patients died during follow-up.

The detection of at least 2 DTC per 1.5x106 mononuclear BM cells was significantly associated with a lower local recurrence free survival (log-rank: p=0.023) whereas there was no significant difference in distant disease free survival (p=0.315) and overall survival (p=0.083).

Discussion

For the first time, we were able to show that DTC-detection in DCIS patients is associated with local recurrence.

The number of distant metastases in women without invasive local recurrence detected in this cohort was comparable to earlier findings at different centers. This study warrants further investigations concerning evolutionary relationship between primary tumor, minimal residual disease, local recurrence and clinically detectable macrometastases.

Citation Format: Walter VP, Taran F-A, Wallwiener M, Brucker SY, Hartkopf AD. Detection of disseminated tumor cells in DCIS patients impacts local recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-16.