bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B38: Developing a functional genomics platform to interrogate rare pediatric cancers
Authors: Hong Andrew L. , Cowley Glenn S. , Tseng Yuen-Yi , Cheah Jaime H. , Jonas Oliver , Doshi Mihir B. , Kynnap Bryan D. , Oh Coyin , Meyer Stephanie , Clemons Paul , Burger Michael , Vazquez Francisca , Weir Barbara , Kryukov Gregory V. , Church Alanna , Imamovic Alma , Tsherniak Aviad , Bielski Craig , Crompton Brian , Mullen Elizabeth , Roberts Charles , Rodriguez-Galindo Carlos , Janeway Katherine A. , Stegmaier Kimberly , Hummelen Paul van , Langer Robert , Garraway Levi A. , Schreiber Stuart L. , Root David E. , Boehm Jesse S. , Hahn William C.
Published: May 2016

Of pediatric solid tumors, as many as 10% of tumors are categorized as rare. Many of these rare tumors lack standard effective known therapy. The ability to identify vulnerabilities for many rare tumors has been significantly limited by the lack of in vitro and in vivo models. Furthermore, current approaches to study such vulnerabilities are usually limited to a specific compound or target. Our objectives were 1) to develop a platform to collect tumor samples and generate in vitro models and 2) to develop systematic and orthogonal approaches focused on currently known druggable cancer targets to identify vulnerabilities in these difficult to treat cancers. We have developed a proof of concept cell line from a patient who succumbed to progressive undifferentiated sarcoma treated on an aggressive multi-therapy regimen. This cell line, in its early passages, has novel gene fusions that match that of the primary tumor. Furthermore, even at early passages, this cell line was amenable to high throughput functional screens. Using a targeted pooled shRNA screen (employing matched seed controls) and an analogous CRISPR screen we identified dependencies to XPO1 and CDK4. In parallel, compounds against these targets were identified in a small molecule compound screen. These targetable dependencies were further validated in vivo with a micro-dosing device. These observations identify new targets in this rare malignancy. Furthermore, this suggests that the interrogation of patient derived cell lines facilitates the identification of testable therapeutic approaches.

Citation Format: Andrew L. Hong, Glenn S. Cowley, Yuen-Yi Tseng, Jaime H. Cheah, Oliver Jonas, Mihir B. Doshi, Bryan D. Kynnap, Coyin Oh, Stephanie Meyer, Paul Clemons, Michael Burger, Francisca Vazquez, Barbara Weir, Gregory V. Kryukov, Alanna Church, Alma Imamovic, Aviad Tsherniak, Craig Bielski, Brian Crompton, Elizabeth Mullen, Charles Roberts, Carlos Rodriguez-Galindo, Katherine A. Janeway, Kimberly Stegmaier, Paul van Hummelen, Robert Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root, Jesse S. Boehm, William C. Hahn. Developing a functional genomics platform to interrogate rare pediatric cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B38.
Abstract B46: MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma
Authors: Ribeiro Diogo , Westermark Ulrica , Klarqvist Marcus , Lovén Jakob , Henriksson Marie Arsenian
Published: May 2016

Neuroblastoma is the most common extra-cranial solid tumor in children and arises from neural crest cells involved in the development of sympathetic nervous tissue. This childhood tumor is characterized by heterogeneity and amplification of the MYCN oncogene is highly associated with aggressive tumors and poor outcome. The aim of this study was to investigate the role of the MYCN-driven miR-17-92 cluster in neuroblastoma pathogenesis. In order to identify putative targets of miR-17-92 we performed in silico prediction analysis and found that miR-17-92 target sites are significantly enriched in the nuclear hormone receptor (NHR) super family, indicating a role for hormonal regulation in neuroblastoma tumorigenesis. Importantly, high expression of several of the NHRs correlated with increased event-free survival of neuroblastoma patients. By using non-MYCN amplified neuroblastoma cells with a tet-regulatable miR-17~92 we could verify a differentially expressed NHR profile in induced compared to uninduced cells. Interestingly, one of the most significantly dowregulated NHRs was the glucocorticoid receptor (GR). Moreover, luciferase reporter assays containing the wildtype or mutated 3'UTR from the gene encoding GR demonstrate that it is a direct target of miR-17~92. Importantly, both MYCN and miR17~92 are able to downregulate GR. We further show that activation of GR signaling by dexamethasone induces differentiation markers and contributes to neural differentiation. Inhibition of MYCN activity and activation of GR signaling induced a significant reduction in tumor growth in a xenograft model of neuroblastoma. Taken together, our findings indicate an important role for miR-17-92 cluster in regulation of NHRs in neuroblastoma biology, with important implications for future therapeutic approaches in patients with MYCN-amplification.

Citation Format: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Lovén, Marie Arsenian Henriksson. MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B46.
Abstract IA02: Human ES cells for modeling brain cancer
Authors: Tabar Viviane
Published: May 2016

Diffuse Intrinsic Pontine Gliomas (DIPG) are a highly aggressive tumor of the brainstem occurring primarily in children. The outlook of patients with this disease is particularly dire due to the tumor's inaccessible location and its lethal course over one or two years. Recent sequencing data identified, for the first time in human cancer, heterozygous mutations in the histone H3 that create a lysine to methionine amino acid substitution. Using a human ES-based platform, we demonstrate the exquisitely cell-context specific oncogenic role of the H3K27M mutation. The model recapitulated the histological features and in vivo progression of the human tumor, as well as its transcriptomal and epigenetic profile. Genome wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive state, with evidence of major modifications of histone marks at master regulatory genes.

Drug screens in the ES model identified a compound that targets menin, a protein with multiple partners the mixed leukemia lineage protein MLL. The compounds have been validated in patient derived DIPG cell lines and are undergoing intense preclinical assessments. The ES model, coupled with more recent gene editing technology, provides a very powerful platform for the dissection of the requirements of neoplastic transformation in specific tumors, the specification of cells of origin, as well insight into the downstream effectors of individual and combined mutations.

Human pluripotent stem cells have an excellent potential as platform for modeling cancer. Work to extend these findings to additional mutations and tumor types is ongoing.

Ref. Funato et al. Science. 2014 Dec 19;346 (6216)

Citation Format: Viviane Tabar. Human ES cells for modeling brain cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA02.
Abstract IA03: Insights into the origins and pathogenesis of embryonal rhabdomyosarcoma
Authors: Drummond Catherine J. , Devine Daniel , Garcia Matthew R. , Hatley Mark E.
Published: May 2016

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. RMS includes two histolopathologic subtypes: alveolar RMS, driven by the fusion protein PAX3/7-FOXO1, and embryonal RMS (ERMS), which is genetically heterogeneous. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle such as the prostate, bladder, biliary tree and the omentum.

Previously, we showed that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of an adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human ERMS. In this model, tumorigenesis occurs with high penetrance (~80%), is early onset (by 2 months of age), and is restricted to the head and neck. Also, unlike previous RMS models, this model requires no additional background mutations, such as inactivation of p53, and drives only ERMS neoplasia. We illustrated that the transcriptome of the aP2-Cre;SmoM2 tumors recapitulates both other mouse ERMS models as well as human ERMS.

With the short latency and anatomic restricted tumor location, we sought to leverage this model to explore the cell of origin. Lineage tracing the aP2-Cre with reporter mice illustrated aP2-Cre expression in both brown and white adipose tissue as well as a discrete population of cells lying between skeletal muscle fibers but not beneath the laminin sheath of the muscle fibers. These aP2-lineage cells are distinct from Pax7-positive skeletal muscle stem cells or satellite cells. The aP2-lineage cells do not contribute to myotube formation in vitro. When compared to aP2-Cre;R26-Tom mice, the addition of oncogenic SmoM2 (aP2-Cre;R26-Tom;SmoM2) results in embryonic expansion of the aP2-lineage interstitial muscle cells. Our findings suggest that non-skeletal muscle progenitors are a potential cell of origin for Sonic Hedgehog-driven ERMS.

Citation Format: Catherine J. Drummond, Daniel Devine, Matthew R. Garcia, Mark E. Hatley. Insights into the origins and pathogenesis of embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA03.
Abstract IA09: Use of novel treatments for childhood ALL
Authors: Gore Lia
Published: May 2016

Overall and disease free survival for childhood acute lymphoblastic leukemia (ALL) has continued to improve such that there are now subsets of patients with ALL who have a greater than 98% chance for cure, while some have significantly poorer outcomes and remain refractory to conventional treatments. Prognostic factors are refined sufficiently to allow risk-directed categorization and disease treatment allocation, which for some patients may mean less intensive therapy and the potential for fewer short- and long-term side effects, while advances in molecular and genomic diagnostics are increasingly being used to consider alterations in primary therapy for higher risk patients. Recent developments in therapies for childhood ALL such as those presented at this meeting have altered the landscape of available options for the treatment of relapsed ALL in particular, and increasingly, practicing pediatric oncologists are challenged to place these new treatments into the context of currently established therapies and prioritize the options for relapsed patients specifically.

Immunotherapy and strategies using chimeric antigen T-cells, virus-specific T-cells, bi-specific antibodies (T-cell engaging and otherwise), and immunotoxins have greatly increased in availability and sophistication, and are now more widely available, with ever-increasing potential applications, although to date, they have not been applied to newly diagnosed patients. Simultaneously, the number of available new therapeutic options is large enough that meaningful clinical trials can be difficult to conduct based on the proportion of agents to the number of available patients eligible for such trials. A pressing challenge to the field is to begin to place these therapies in the context of more conventional approaches to the currently highly successful treatment of ALL for a large majority of affected patients, and to continue to evaluate both the short- and long-term consequences of newer treatments both alone and in combination with other more conventional agents.

Discussion about what constitutes a truly novel therapy and examples of currently available experimental therapies for childhood ALL will be reviewed. The context of these treatments to future strategies and trial opportunities for both single agent and combination explorations will be discussed.

Citation Format: Lia Gore. Use of novel treatments for childhood ALL. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA09.
Abstract IA12: SWI/SNF (BAF) complex mutations in cancer
Authors: Roberts Charles W. M.
Published: May 2016

Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.

My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented.

Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA12.
Abstract IA24: Science of surviving cancer: Lessons learned from our cancer survivors
Authors: Bhatia Smita
Published: May 2016

The 5-year overall survival rate for childhood cancer now exceeds 80%. As a result of this improvement in survival, the number of childhood cancer survivors now exceeds 375,000. The increasing number of long-term survivors is attended by a growing awareness that many will develop health conditions as a direct or an indirect consequence of their cancer therapy. While some of these conditions occur during therapy and persist well after the therapy has been completed (such as steroid-induced osteonecrosis, or alkylating agent /radiation-induced hypogonadism), many outcomes are not evident until 10-20 years later, such as subsequent malignant neoplasms (SMNs) and anthracycline-related late onset congestive heart failure (CHF). Individuals exposed to radiation and chemotherapy are vulnerable to long-lasting organ toxicity. While clear and unambiguous associations exist between therapeutic exposures and specific complications, considerable inter-individual variability is observed in the risk of developing an outcome for any given exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the inter-individual variability. Thus, it becomes imperative to understand the individual variability in: i) the internal dose of the therapeutic agent; ii) the biologically effective dose; iii) the alterations in structure or function of the tissue or organ; and iv) the consequent development of preclinical disease, in order to understand the pathogenesis of therapy-related complications, and also develop a better idea of the individual susceptibility. Over the past decade, there have been several reports describing the role of genetic susceptibility in anthracycline-related CHF, in chemotherapy-related leukemia, radiation-related solid SMNs, and corticosteroid-related osteonecrosis. These studies have varied in their investigative approach – from a candidate gene investigation to a genome-wide association study. Understanding the etiology and pathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life.

Citation Format: Smita Bhatia. Science of surviving cancer: Lessons learned from our cancer survivors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA24.
Abstract IA25: Prevention in survivors: Reducing the “cost” of surviving childhood cancer
Authors: Diller Lisa R.
Published: May 2016

Childhood cancer survivors are at significantly increased risk of treatment-related chronic disease and subsequent malignancy. Preventive intervention and screening can hopefully reduce the morbidity or mortality of these late-occurring illnesses. Screening for secondary cancer based upon prior exposures has been implemented for detection of early radiogenic breast cancers, skin cancers and GI malignancies. In adults without a history of childhood cancer, prevention strategies for diseases such as breast cancer and coronary artery disease have been investigated, but there is little evidence for the use of population-based strategies in childhood cancer survivors. We will review the role of primary and secondary prevention in childhood cancer patients and survivors. How have reduction of therapy studies reduced risk of late sequelae? What prevention interventions have been studied in survivors and what is the ongoing research in survivors? Data from studies of breast cancer screening with MRI and prevention with tamoxifen will be presented. Can we draw experience in prevention in other high-risk groups to apply to childhood cancer survivors? We will present results of our unique survivorship Markov model, which can help estimate the impact of screening strategies on outcome. Finally, prevention strategies carry potential risk – how do we help patients make decisions and help them understand risk?

Citation Format: Lisa R. Diller. Prevention in survivors: Reducing the “cost” of surviving childhood cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA25.
Abstract IA26: Oncogenic mechanisms in diffuse intrinsic pontine gliomas
Authors: Silveira Andre B. , Kasper Lawryn H. , Larson Jon D. , Zhu Xiaoyan , Diaz Alexander K. , Baker Suzanne J.
Published: May 2016

Diffuse intrinsic pontine glioma (DIPG) is a devastating disease with no effective cures. DIPG arises in the brainstem and is found almost exclusively in children. Mutations in canonical cancer signalling pathways including the RTK/RAS/PI3K pathway, the Tp53 pathway, and the CDK4/6 G1 checkpoint occur in DIPGs, targeting different effectors within these pathways and resulting in significant genetic heterogeneity between tumors. However, genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. Recurrent mutations of the BMP receptor ACVR1/ALK2 are found in 25-30% of DIPGs, and are further restricted to the youngest patients, highlighting critical connections between development and gliomagenesis. The molecular hallmark of DIPGs is frequent recurrent somatic mutation in histone H3. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs. These recurrent mutations provide clear evidence of an important role for chromatin regulation in DIPG disease pathogenesis, and present a unifying molecular mechanism driving DIPG. We have evaluated the contribution of H3.3 K27M mutation to DIPG tumor growth in vitro to gain insights into molecular mechanisms of oncogenic activity, and to assess the potential of histone H3 mutation as a therapeutic sensitivity in this incurable brain tumor.

Citation Format: Andre B. Silveira, Lawryn H. Kasper, Jon D. Larson, Xiaoyan Zhu, Alexander K. Diaz, Suzanne J. Baker. Oncogenic mechanisms in diffuse intrinsic pontine gliomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA26.
Abstract IA28: New targeted approaches for high-risk pediatric malignancies
Authors: Stegmaier Kimberly
Published: May 2016

While significant progress has been made in treating many pediatric malignancies, cancer remains the leading cause of death from disease in children. A number of childhood cancer subtypes remain particularly recalcitrant to dose-intensified cytotoxic treatment suggesting that new approaches are needed. Initial optimism that massively parallel sequencing efforts would reveal imminently targetable lesions has been tempered by a major finding that pediatric cancers often have simple genomes. While a signature mutation is frequently present, the product is often considered a difficult drug target, such as an aberrant transcription factor. Thus, the hope that cancer can be treated with combinations of drugs targeting specific gene mutations is unlikely to be imminently viable for most pediatric cancers.

We hypothesized that while there is a notable paucity of events in easily druggable enzymes, a small number of sentinel lesions in an otherwise quiet genome may enable the discovery of synthetic lethal relationships with these key genetic events. Thus, we are applying unbiased approaches to identify key dependencies in pediatric cancers using functional genomic screening (shRNA and CRISPR) and chemical genomic screening. The primary goal is to connect key genetic lesions or disease lineages to new gene targets or small-molecule perturbations in the highest risk subtypes of pediatric cancers. Illustrative examples of our early findings will be presented.

Citation Format: Kimberly Stegmaier. New targeted approaches for high-risk pediatric malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA28.
Abstract BL2: Lessons learned from an expedition exploring the world of HER2 positive breast cancer
Authors: Piccart M
Published: May 2016

HER2 positive breast cancer (BC) is often cited as a model of “treatment individualization”.

This presentation will attempt to review the biomarker research efforts for this disease, with a special focus on the work coordinated by the Institut Jules Bordet in the advanced setting and the work of the Breast International Group (BIG) in the adjuvant setting.

Biomarker (BM) exploration in the context of the CLEOPATRA and EMILIA trials has highlighted the poor prognosis associated with PiK3CA mutations, but has failed to identify any predictive BM beyond HER2. Our group, in collaboration with Dutch cancer centers, has prospectively “imaged” 57 patients under T-DM1 treatment using both “target imaging” (trastuzumab-zirconium PET) and FDG-PET: 4 imaging patterns have emerged, providing a striking illustration of advanced disease heterogeneity. Ongoing work will confirm whether these molecular imaging patterns can help to refine the selection of anti-HER2 therapies and, more specifically, support early discontinuation of expensive drug treatment that is unlikely to benefit patients.

The translational research programs of BIG in the context of its (neo)adjuvant trials for HER2-positive BC will be reviewed and put into the context of findings by other researchers as well as the real needs of patients, which include the following: Can aggressive chemotherapy be avoided ? Can duration of treatment be shortened? Who does not need treatment “escalation”?

Citation Format: Piccart M. Lessons learned from an expedition exploring the world of HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BL2.
Abstract BS2-2: Roles of epigenetic regulation in breast cancer development
Authors: Green MR
Published: May 2016

Changes to the genomic DNA sequence, called mutations, are known to play a critical role in the development of cancer. However, increasing evidence indicates that epigenetic changes (heritable cellular changes in gene expression that do not involve alterations in the DNA sequence) also make important contributions to tumorigenesis. For example, promoter hypermethylation plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone ubiquitination, methylation and acetylation, affect local chromatin structure and regulate gene transcription. Using genome-wide RNA interference screens, we are uncovering epigenetic modulators that play important roles in breast cancer development and progression. The results of these studies are expected to shed light on the role of epigenetic regulation in breast cancer, and suggest new therapeutic approaches.

Citation Format: Green MR. Roles of epigenetic regulation in breast cancer development. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BS2-2.
Abstract ES3-3: Post-mastectomy breast reconstruction: defining the effects of adjuvant treatment modalities on surgical outcomes
Authors: Sbitany H
Published: May 2016

Post-mastectomy breast reconstruction is routinely offered immediately at the time of mastectomy, and can be performed using prosthetic or autologous techniques. Successful surgical outcomes are routine with these procedures, but can be complicated when adjuvant treatment modalities for breast cancer are employed. The most common adjuvant treatments effecting outcomes in post-mastectomy breast reconstruction are radiation, chemotherapy/hormonal therapy, and axillary lymph node dissection.

Adjuvant radiation therapy has been shown to increase the complication rate in prosthetic breast reconstruction, specifically with increased rates of implant infection (22%, p=0.0), full-thickness mastectomy skin necrosis (11.5%, p=.001), and expander/implant removal (17.7%, p=0.0). Such complication rates are improvements over earlier reports, likely due to altered incision placement in nipple sparing mastectomy to the periareolar area, waiting at least 6 months following radiation completion prior to implant exchange, and the use of acellular dermal matrices (shown on multivariate analysis to reduce explantation rates in setting of radiation). With autologous breast reconstruction, adjuvant radiation has been shown to increase rates of volume flap volume loss (19.75%, p=.0001), but not flap loss rates (1.23%, p=1).

The use of adjuvant chemotherapy and hormonal therapy has not been shown to negatively impact outcomes in prosthetic breast reconstruction, to any statistically significant amount. This includes tamoxifen and herceptin therapy. Similarly, the use of hormonal therapy does not significantly effect overall outcomes in autologous breast reconstruction.

The use of axillary lymph node dissection has been shown to have a significant negative impact on outcomes in prosthetic breast reconstruction, compared to sentinel lymph node biopsy. On multivariate analysis, axillary lymph node dissection increased rates of breast implant loss (RR 2.0, p=.021), relative to sentinel lymph node biopsy. This is due to the decreased lymphatic drainage of remaining breast tissue, and resultant increase in infection and implant loss.

Citation Format: Sbitany H. Post-mastectomy breast reconstruction: defining the effects of adjuvant treatment modalities on surgical outcomes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES3-3.
Abstract ES7-3: Adjuvant endocrine therapy: Is the price of forever too high?
Authors: Niravath P
Published: May 2016

Over the past several years, new data has emerged which shows the added benefit of more aggressive endocrine therapy for both pre- and post- menopausal women. With increasing use of ovarian suppression in pre-menopausal women and extended adjuvant endocrine therapy across the board, we are seeing subsequent increased toxicity. While these more intensive treatments do offer benefit in certain high-risk populations, they can also significantly decrease quality of life for many women. This talk will discuss how to carefully weigh the risks and benefits of an increasingly aggressive endocrine therapy approach for each patient. We will also discuss how to tailor treatment options to the individual patient and her cancer.

Citation Format: Niravath P. Adjuvant endocrine therapy: Is the price of forever too high?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES7-3.
Abstract ES9-1: Role for IGF/Insulin signaling in breast cancer
Authors: Yee D
Published: May 2016

Because insulin regulates glucose homeostasis, there has been extensive study into the molecular mechanisms of action of the insulin signaling system. Besides insulin, additional ligands, insulin-like growth factor (IGF) – I and –II and specific receptors for these ligands regulate cellular biology. The receptors share a similar structure and function. Once ligand binds the extracellular domain, a conformational change occurs allowing autophosphorylation of the intracellular tyrosine kinase domains and subsequent activation of multiple signaling pathways that ultimately result in cellular glucose uptake. Type 2 diabetes mellitus (T2D) results from deficient insulin receptor (InsR) signaling and subsequent elevation of serum glucose with compensatory attempt at regulating this pathophysiology by increased insulin production by the pancreas. While the etiology of T2D is complex and multi-factorial, obesity and insulin resistance are epidemiologically and mechanistically linked. Insulin was one of the first peptide growth factors known to stimulate breast cancer proliferation. Epidemiological data link obesity, metabolic syndrome (hyperinsulinemia), and elevated levels of IGFs to breast cancer risk and poor outcome for women diagnosed with breast cancer. These data, in part, led to the development of multiple targeted therapies for breast cancer. Receptor targeting of IGF-receptor signaling was not successful in hormone receptor (HR) positive breast cancers possibly because drugs designed to target this receptor disrupted the negative feedback of this endocrine system and resulted in the elevation of serum insulin levels. Since InsR was not affected by anti-IGF receptor drugs, the potential that InsR was stimulated by these drug treatments could explain their failure. In contrast to receptor targeting strategies, the inhibition of downstream signaling pathways, such as mTORC1, have been successful in HR-positive breast cancer. Preclinical and clinical data have revealed complex intracellular and endocrine feedback pathways that affect the ability of any single targeted drug to effectively disrupt signals from this ligand-receptor family. This session will discuss combination strategies based on clinical and preclinical studies that could translate into effective drug therapies to disrupt this signaling system.

Citation Format: Yee D. Role for IGF/Insulin signaling in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-1.
Abstract MS2-2: Genomics to personalize therapy of metastatic breast cancers
Authors: André F
Published: May 2016

Genomic studies have shown that breast cancer includes large number of rare genomic segments. This led to the development of precision medicine where sequencing could be used to identify drivers in individuals, that would be treated accordingly. 10 to 20 molecular alterations are being investigated in the context of biomarker-driven therapeutic trials. This includes PIK3CA, AKT1, ERBB2, PTEN, BRCA1/2, ESR1 mutations, FGFR1, CCND1 amplifications, AR expression. Beyond the question of clinical utility of detecting these variants, there are several challenges that precision medicine is facing in breast cancer.

The first challenge will be to better define which genomic alterations are drivers in individuals and how to target them. The recent failures of prospective trials testing precision medicine (SAFIR01, SHIVA) highlights the need to better understand what defines a targetable alteration. These trials also pointed out the need to target the molecular alterations, rather than the pathway. Also, it's important to better understand the role that alterations on multiple drivers could play on resistance. As illustration, several reports suggest that PIK3CA mutations could be associated to a lower sensitivity to dual Her2 inhibition in neoadjuvant setting.

The second challenge will be to generate genomic tests that predict the sensitivity of therapies that target pathways, like mTOR or CDK4 inhibitors. To this regards, gene expression looks particularly attractive since it allows quantifying pathway activation.

The third challenge will be to predict earlier the resistance to targeted therapies. The development of circulating DNA as a diagnostic tool could be useful for early diagnosis of resistance. Clinical trials testing this technology are currently starting.

Finally, one of the major challenge will be to integrate immunotherapeutics in the application field of precision medicine. High mutational loads and neoantigen expression could predict efficacy of immunotherapeutics. Further combination with targeted therapies should be rationalized based on genomics.

Overall, while candidate biomarkers exist and technologies are available, precision medicine failed to deliver until now for patients with metastatic breast cancer. Nevertheless, ongoing randomized trials testing drugs according to genomic alterations should open the door of treatment decisions based on genomics for breast cancer patients.

Citation Format: André F. Genomics to personalize therapy of metastatic breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr MS2-2.
Abstract OT1-03-11: Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140)
Authors: Chavez-MacGregor M , Barlow WE , Pusztai L , Goetz MP , Rastogi P , Ganz PA , Mamounas EP , Paik S , Bandos H , Gralow J , Lew DL , Hortobagyi GN
Published: May 2016

Background: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in BC. This pathway is associated with resistance to endocrine therapies among HR+ tumors. Everolimus, an mTOR-inhibitor, increases the biological activity of endocrine therapy. S1207 evaluates the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: Specific aims/ design: Randomized phase III double-blinded, placebo-controlled trial. Primary objective is to assess whether the addition of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk, HR+ BC. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and QoL. Patients are randomized to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or placebo. Submission of tissue specimens/blood samples is required for translational studies Eligibility criteria: Patients with histologically confirmed HER2-negative and HR+ invasive BC treated with surgery, adjuvant chemotherapy and radiation therapy (if indicated) are eligible if they have: node-negative disease and tumors >2cm and a recurrence score (RS) >25; 1-3 positive nodes and RS >25 or grade 3 in the absence of RS; >4 positive lymph nodes regardless of RS. Patients >1 positive lymph node after completing neoadjuvant chemotherapy are eligible. Statistics/Target accrual:Parallel randomization design with equal allocation to the two treatment groups, the study will randomize 3,500 patients. All analyses are intent-to-treat with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years. Support: NIH/NCI NCTN Grants CA180888, 180819, 180868, 180821,180822 189867, and in part by Novartis Clinical trial information: NCT01674140.

Citation Format: Chavez-MacGregor M, Barlow WE, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Gralow J, Lew DL, Hortobagyi GN. Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-11.
Abstract OT3-01-01: HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1)
Authors: Miller K , Cortes J , Hurvitz SA , Krop IE , Tripathy D , Verma S , Riahi K , Reynolds JG , Wickham T , Molnar I , Yardley DA
Published: May 2016

Background: Although HER2-targeted therapies such as pertuzumab and T-DM1 have improved patient outcomes, treatment resistance typically occurs. MM-302 is a HER2-targeted liposomal doxorubicin in development by Merrimack Pharmaceuticals. In a Phase 1 study, patients with HER2-positive metastatic breast cancer (MBC) were treated with MM-302 alone and in combination with trastuzumab with or without cyclophosphamide. MM-302 had an acceptable safety profile and promising efficacy was observed in patients not previously exposed to an anthracycline.

Trial design: HERMIONE (NCT02213744) is a randomized Phase 2, two-arm, open-label trial designed to evaluate if MM-302 can address an unmet medical need in patients with anthracycline naïve, trastuzumab-, pertuzumab- and T-DM1-pretreated HER2-positive locally advanced breast cancer (LABC)/MBC. Patients are randomized 1:1 to receive MM-302 (30mg/m2, Q3W) plus trastuzumab (6mg/kg, Q3W) or chemotherapy of physician's choice (vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6mg/kg, Q3W).

Eligibility criteria: Centrally confirmed HER2-positive LABC/MBC, no prior anthracycline exposure, prior trastuzumab in any setting, prior pertuzumab and T-DM1 in the LABC/MBC setting, unlimited prior lines of therapy, ECOG 0-1 and LVEF ≥50%. CNS metastases are permitted if stable and without symptoms or steroids for 4 weeks.

Specific aims: The primary endpoint is independently assessed progression free survival (PFS). Secondary endpoints include investigator assessed PFS, overall survival, response rate, safety and patient related outcomes.

Statistics: 250 patients will be enrolled to observe 191 PFS events for 90% power to detect a Hazard Ratio of 0.625. The MM-302 arm will be compared to the control arm on the primary endpoint of PFS using a stratified log-rank test at one-sided 0.025 level.

Accrual status: First patient in was December 2014 and enrollment is expected to be complete in late 2016. Sites are open in the US, Canada and Western Europe and are currently enrolling patients.

Citation Format: Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, Riahi K, Reynolds JG, Wickham T, Molnar I, Yardley DA. HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-01.
Abstract OT3-02-08: Scalp cooling alopecia prevention trial (SCALP) for patients with early stage breast cancer
Authors: Nangia JR , Wang T , Rude M , Osborne C , Papish S , Abraham J , Holmes F , Savin M , Paxman R , Hilsenbeck SG , Osborne CK , Rimawi M
Published: May 2016

Background

Adjuvant chemotherapy treats micro-metastatic disease and decreases the risk of breast cancer recurrence. However, it may be associated with distressing side effects, including alopecia. Women with breast cancer rate chemotherapy-induced alopecia as one of the most severe, troublesome, and distressing side effects of chemotherapy. In many countries, scalp cooling has been introduced to prevent or reduce chemotherapy-induced alopecia. The theory is that scalp cooling causes cutaneous vasoconstriction, which reduces blood flow to the hair follicles during peak plasma concentrations of the chemotherapeutic agents and therefore reduces cellular uptake of these agents. It also results in reduced biochemical activity, which makes hair follicles less susceptible to the damage of the chemotherapy agents. Historically success rates are have been variable, but based on non-randomized studies, scalp cooling appears to be effective in preventing chemotherapy-induced alopecia especially in more recent studies.

Methods

We are conducting a prospective multi-center randomized controlled non-blinded trial to evaluate the safety and efficacy of the Orbis Paxman Hair Loss Prevention System in reducing the incidence of chemotherapy-induced alopecia. Women with stage I-II breast cancer who will receive neoadjuvant or adjuvant anthracycline- or taxane-based chemotherapy, for at least four cycles are eligible. Participants are randomized in a 2:1 ratio to scalp-cooling or no cooling. Scalp-cooling is done using the Orbis Paxman Hair Loss Prevention System prior to, during and after each chemotherapy administration. The primary efficacy endpoints are hair preservation, defined as CTCAE v4 alopecia <2, and device safety. Two hundred and thirty five (235) patients are planned to be enrolled which will provide 85% power to detect a 20% difference in hair preservation, 15% in control group and 35% in scalp-cooling group . Secondary endpoints include: wig/scarf use and quality of life assessed by the EORTC QLQ-30, HADS and BIS. Study participants will be followed for 5 years post-study for time to first recurrence, overall survival, site of first recurrence, and incidence of isolated scalp metastasis.

Citation Format: Nangia JR, Wang T, Rude M, Osborne C, Papish S, Abraham J, Holmes F, Savin M, Paxman R, Hilsenbeck SG, Osborne CK, Rimawi M. Scalp cooling alopecia prevention trial (SCALP) for patients with early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-08.