Invited Speaker Abstracts最新文献

{"title":"Abstract ES12-2: Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis","authors":"Rong Li","doi":"10.1158/1538-7445.SABCS18-ES12-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES12-2","url":null,"abstract":"Breast cancer risk is significantly elevated for women who carry germ-line mutations in the tumor suppressor gene BRCA1. BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. These precancerous cells of origin are defective in luminal differentiation in BRCA1 mutation carriers before any clinical evidence of cancer. While BRCA1 is best known for its functions in double strand break DNA repair and response to DNA replication stress, it is unclear whether loss of these ubiquitously important functions of BRCA1 is sufficient to account for lineage-specific breast tumor development in BRCA1 mutation-carrying women. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention. Recent discoveries from others and us challenge the prevailing DNA repair/replication-centric paradigm. First, in vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Using breast tissue of cancer-free BRCA1 mutation-carrying women, we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 59 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1 knockout mouse mammary epithelium. Of note, this BRCA1/COBRA1 interaction occurs in a DSB repair-independent manner. Based on these findings, we suggest that as part of its tumor suppressor activity, BRCA1 promotes luminal epithelial differentiation by mitigating Pol II pausing-dependent transcriptional stress at luminal fate genes. We further propose that accumulation of transcriptional stress in BRCA1-deficient luminal cells redirects luminal transcription and alters luminal homeostasis, which ultimately contributes to lineage-specific BRCA1-associated tumorigenesis. Citation Format: Li R. Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES12-2.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"44 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134331830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES9-2: Updates on immunotherapy for TNBC","authors":"S. Adams","doi":"10.1158/1538-7445.SABCS18-ES9-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES9-2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133873454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES11-2: Current status of diagnosis, monitoring, and non-surgical management of lymphedema","authors":"S. Mclaughlin","doi":"10.1158/1538-7445.SABCS18-ES11-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES11-2","url":null,"abstract":"Lymphedema (LE) is a common but underreported complication of breast cancer treatment since most studies lack baseline and follow-up measurements or follow-up that is long enough to adequately record true incidence. Contemporary prospective randomized trials continue to document the occurrence of lymphedema after any axillary treatment and note that combination therapy with axillary surgery and radiation nearly doubles LE risk. Over the last 5 years clinicians have witnessed a paradigm shift in the diagnostic practices of LE with concerted efforts focusing on early detection as opposed to reactionary interventions. Controversy however has existed over how to define and diagnose LE and as such the literature surrounding diagnosis is heterogeneous with respect to incidence and recommendations. Existing guidelines emphasize the need for routine monitoring for LE and the critical importance of baseline, bilateral, and longitudinal limb assessments but do not embrace one measurement technique. A growing body of prospective observational data is systematically challenging the value of precautionary behaviors. Further, prospective randomized data demonstrates exercise does not promote the development of LE. Complex decongestive therapy remains the cornerstone of non-surgical LE treatment. With the NCI predicting over 4 million breast cancer survivors in the US by 2024, lymphedema is potentially a significant public health burden. Citation Format: McLaughlin S. Current status of diagnosis, monitoring, and non-surgical management of lymphedema [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES11-2.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115268662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES4-3: Techniques and technical considerations","authors":"F. Vicini","doi":"10.1158/1538-7445.SABCS18-ES4-3","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES4-3","url":null,"abstract":"Purpose: Partial breast irradiation (PBI) treats the lumpectomy cavity and a margin of adjacent breast tissue allowing for a reduction in treatment volume, duration and potentially toxicity. Body: Multiple PBI techniques are available. Interstitial brachytherapy (IB) represents the oldest PBI technique; mature data from randomized trials are available with 5-10 year follow-up and demonstrate comparable local control and toxicity profiles. Technically, multiple target volume definitions are currently utilized. Applicator based brachytherapy has evolved from single-lumen applicators, increasing the degrees of freedom for treatment planning. Prospective, non-randomized 5 year data are available with applicator based brachytherapy, demonstrating low rates of recurrence, comparable rates of toxicity, and high rates of excellent/good cosmetic outcomes. The treatment volume for applicator based brachytherapy is 1 cm surrounding the device, with adjustments for the skin and chest wall. External beam radiation therapy includes 3D-CRT, IMRT and proton based techniques. Data from 3D-CRT studies have suggested higher toxicities and inferior cosmetic outcomes. However, randomized studies evaluating IMRT PBI have not, demonstrating comparable or improved toxicity and cosmetic outcomes. Intraoperative radiation therapy (IORT) is unique as two randomized trials have evaluated IORT and found higher rates of local recurrence as compared to WBI. Low-energy IORT delivers 25-30% of prescription at 1 cm, different from other PBI techniques while electron IORT allows for modulation of energy/depth. Currently, ASTRO PBI guidelines do not recommend low-energy IORT off protocol and electron IORT only for suitable risk patients, while ABS guidelines do not recommend IORT off trial. Finally, newer PBI techniques include non-invasive image-guided breast brachytherapy and permanent seed implants. As with all PBI techniques, use of guidelines for the application of PBI is encouraged for patient selection and the application of well-established dosimetric criteria for target coverage and normal tissue tolerances. Conclusions: Partial breast irradiation represents a standard of care strategy for appropriately selected patients. Citation Format: Vicini F. Techniques and technical considerations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES4-3.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"99 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130450753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES8-2: New data on hormones and risk of breast cancer","authors":"S. Hankinson","doi":"10.1158/1538-7445.sabcs18-es8-2","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-es8-2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126992196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract MS1-2: Deep learning systems for reading mammograms and breast tomosynthesis","authors":"N. Karssemeijer","doi":"10.1158/1538-7445.sabcs18-ms1-2","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ms1-2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125726760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES6-2: PI3K in breast cancer, glutamine changes and methionine addiction","authors":"A. Toker","doi":"10.1158/1538-7445.SABCS18-ES6-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES6-2","url":null,"abstract":"Mutations in the PI 3-kinase and AKT signaling pathway are highly prevalent in breast cancer. In luminal, estrogen receptor-positive breast cancer patients, oncogenic mutations in PIK3CA, the gene that encodes the catalytic subunit of class 1a PI3K occur with a frequency of approximately 40%. By contrast, inactivating mutations and loss of heterozygosity in the tumor suppressors PTEN and INPP4B that normally terminate PI3K signaling, are found more frequently in basal-like, triple negative breast tumors. Regardless, in all cases the net result is hyperactivation of PI3K/AKT signaling leading to induction of phenotypes associated with malignancy. In spite of the frequency of genetic lesions in the PI3K pathway and the development of potent and specific small molecule inhibitors targeting the PI3K pathway, results from clinical trials with these inhibitors have been disappointing most often due to dose-limiting on-target toxicities. Consequently, numerous combination trials with PI3K inhibitors and other targeted therapies are underway. Separate pre-clinical and clinical efforts have also been initiated targeting PI3K oncogene addition with therapies that impact cellular states and programs, including metabolic pathways and enzymes. The concept that metabolic reprogramming is a feature of all cancer cells, and not merely a byproduct of accelerated growth, goes back to the days of Otto Warburg who in the 1920s proposed that increased levels of aerobic glycolysis followed by lactate fermentation occurs in tumor cells undergoing rapid growth. This so-called 9Warburg effect9 spurred the recent development of numerous drugs that target glycolysis in human tumors, many of which are in clinical trials. Equally promising are strategies that target non-essential amino acid metabolism. The concept of metabolic starvation, whereby one or more metabolite is limiting or removed has gained traction in the field, with the finding that certain non-essential amino acids, particularly glutamine, can be synthesized by normal cells, whereas tumor cells rely on an extracellular supply to the extent that glutamine deprivation sensitizes tumor cells to death. Glutamine is the most widely studied nutrient, other than glucose, in the field of tumor metabolism. The presentation will focus on the intersection of PI3K, AKT and glutamine metabolism in breast cancer, as well as how these pathways modulate methionine dependency in breast cancers that display PI3K pathway hyperactivation. A greater understanding of the mechanisms by which glutamine and methionine sustain cancer cells may lead to the development or repurposing of other successful targeted metabolic therapies and use of the pathway enzymes and metabolites as biomarkers. Citation Format: Toker A. PI3K in breast cancer, glutamine changes and methionine addiction [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Sup","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"65 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122877472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CS1-3: Moderate penetrance mutations: What to do?","authors":"S. Domchek","doi":"10.1158/1538-7445.SABCS18-CS1-3","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-CS1-3","url":null,"abstract":"Genetic testing for breast and ovarian cancer susceptibility has expanded beyond sequencing of BRCA1 and BRCA2. Panel testing has allowed for rapid, affordable, and routine testing of multiple genes simultaneously. There is no one standard “panel” – panels range in types and number of genes tested and panel composition is at the discretion of the ordering provider. Some of the genes commonly included have been long associated with specific genetic syndromes with high lifetime risks of the associated cancers, e.g. mutations in PTEN and Cowden9s Syndrome, TP53 and Li Fraumeni Syndrome, STK11 and Peutz-Jeghers Syndrome, and CHD1 and Hereditary Diffuse Gastric Cancer. The inclusion of these “high penetrance genes” on broad cancer panels can lead to challenges regarding discussion and management when detected in families which are not syndromic (for example, the discussion of prophylactic gastrectomy in individuals with CDH1 mutations and no family history of gastric cancer). Mutations in other genes are clearly associated with breast cancer but with lower lifetime risks than for BRCA1 and BRCA2; for example, the lifetime risk of breast cancer for a PALB2 mutation is approximately 40-50%, whereas for ATM and truncating CHEK2 mutations this risk is 25-30%. Mutations in BRIP, RAD51C, and RAD51D are clearly associated with ovarian cancer with lifetime risks of approximately 10% (significantly lower than for BRCA1 mutations). This lecture will address the current understanding of associated cancer risks for mutations in genes included in hereditary cancer panels with a focus on implications for risk reduction and treatment. Citation Format: Domchek S. Moderate penetrance mutations: What to do? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr CS1-3.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129090823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract BL2: The Challenge of Doing Less","authors":"E. Winer","doi":"10.1158/1538-7445.sabcs18-bl2","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-bl2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128693807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ES5-2: Clinical and molecular profiles to identify who is at risk?","authors":"M. Dowsett","doi":"10.1158/1538-7445.SABCS18-ES5-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES5-2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129033091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}