Invited Speaker Abstracts最新文献

{"title":"Abstract TS2-2: Clinical development of inhibitors of the PI3K pathway","authors":"C. S. Manich","doi":"10.1158/1538-7445.SABCS18-TS2-2","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-TS2-2","url":null,"abstract":"The activation of the PI3K-AKT-mTOR pathway as a mechanism of resistance to different breast cancer treatments has been well described for years at the preclinical level. This observation, together with the high frequency of alterations of this pathway in patients with breast tumors (especially in the luminal subtype such as PI3KCA mutations, loss of PTEN function or AKT mutations) makes this pathway a highly desirable in inhibiting the growth of these tumor types. The first clinical evidence that inhibition of the PI3K-AKT-mTOR pathway leads to increased progression-free survival in metastatic breast cancer came from the BOLERO-2 trial with the mTORC1-targeting agent everolimus, the only PI3K-AKT-mTOR pathway inhibitor approved to date in breast cancer. Potentially better drugs have subsequently been developed and tested. PI3K inhibitors were designed to potentiate the inhibition of the pathway to optimize treatment efficacy and improve the toxicity profile. The first to be developed were the pan-PI3K inhibitors buparlisib and pictilisib. Results from pivotal clinical studies combining fulvestrant demonstrated increased efficacy but at the cost of increased toxicity that was considered clinically unacceptable. None of them consequently eceived approval for breast cancer treatment. It was hoped that Isoform-specific PI3K inhibitors (alpha or beta-sparing) would improve the toxicity profile and increase efficacy, especially in patients with molecular alterations in the PI3K-AKT-mTOR pathway. We are now witnessing interesting times for these drugs since we have seen the results of the two phase III studies with specific pathway inhibitors, taselisib and alpelisib. During this session we will carefully review the results of both studies in terms of efficacy and toxicity profile as well as those from other phase I-II clinical trials with these and other agents. Representing the main challenges in the future, we still have to determine the best strategy to select those patients who will likely derive greater benefit from these therapies as well as establish the context in which they are most effective, taking into account the mechanisms of resistance that PI3K inhibitors can overcome or those that emerge during treatment with these drugs. Citation Format: Saura Manich C. Clinical development of inhibitors of the PI3K pathway [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 TS2-2.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"22 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":"125676325","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 ES8-3: Does breast cancer prevention need an 18th amendment? New evidence on alcohol and breast cancer","authors":"M. Terry","doi":"10.1158/1538-7445.sabcs18-es8-3","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-es8-3","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"8 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":"130031343","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 ES12-1: BRCA2 and control of transcription: R-loop dynamics","authors":"A. Venkitaraman","doi":"10.1158/1538-7445.SABCS18-ES12-1","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES12-1","url":null,"abstract":"Pathogenic germline mutations affecting the breast cancer genes, BRCA1 and BRCA2, predispose to cancers of the breast, ovary, and other tissues with a high penetrance. Cancer pathogenesis in mutation carriers has been linked to genomic instability following inactivation of the essential cellular functions of the encoded BRCA1 and BRCA2 proteins in DNA repair and the restoration of stalled DNA replication (reviewed in Venkitaraman, Science 343, 1470-5 (2014)). Here, I will discuss emerging evidence that links previously unrecognized functions of the BRCA proteins to carcinogenesis, focusing on BRCA2. Increasing evidence indicates that heterozygosity for pathogenic BRCA2 mutations suffices for carcinogenesis in experimental models and in human mutation carriers (eg., Skoulidis et al., Cancer Cell 18, 499-509 (2010); Maxwell et al., Nature Commun 8, 319 (2017); Huang et al., Cell 173, 355-370 (2018)). Heterozygous mis-sense mutations in BRCA2 may act trans-dominantly to interfere with the nuclear transport of BRCA2/RAD51 complexes (Jeyasekharan et al., Nature Str Mol Biol 20, 1191-8 (2013)). We have reported recently a gene-environment interaction that may modify carcinogenesis in BRCA2 mutation carriers, wherein exposure to aldehydes, a pervasive class of endogenous and environmental toxins, selectively proteolyzes BRCA2, inducing haploinsufficiency for DNA repair and replication fork stability in cells bearing heterozygous truncating BRCA2 mutations (Tan et al., Cell 169, 1105-18 (2017)). BRCA2-deficient cells accumulate unscheduled RNA-DNA hybrids (R-loops) and genomic damage through an unexpected role of BRCA2 in promoting the switch from promoter-proximal pausing to transcription elongation by RNA polymerase II (Shivji et al., Cell Rep 22, 1031-1039 (2018)). These emerging functions have implications for the pathogenesis and therapy of cancers arising in patients who carry BRCA2 mutations. Citation Format: Venkitaraman A. BRCA2 and control of transcription: R-loop dynamics [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 ES12-1.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"44 12","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132974345","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 ES3-1: Brain metastases of breast cancer","authors":"P. Steeg","doi":"10.1158/1538-7445.sabcs18-es3-1","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-es3-1","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"84 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":"133078444","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 ES4-1: Partial breast irradiation: Efficacy and patient selection","authors":"C. Coles","doi":"10.1158/1538-7445.SABCS18-ES4-1","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES4-1","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"43 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":"115546747","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 ES9-1: Optimizing treatment of early stage triple negative breast cancer: Clinical challenges and new scientific horizons","authors":"A. Demichele","doi":"10.1158/1538-7445.SABCS18-ES9-1","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES9-1","url":null,"abstract":"“Triple negative” breast cancer (TNBC) as defined by the lack of estrogen and progesterone receptors and absence of Her2-overexpression, is challenging due to its aggressive natural history and limited treatment options. However, significant progress has been made in the last decade in understanding the biological diversity of TNBC, its prognosis and approaches to successful treatment. For example, molecular classification by gene expression studies initially identified a basal molecular subtype enriched for TNBC, which was further refined to additional include 4 major subtypes: basal-like, mesenchymal, luminal androgen receptor and immune-enriched. In addition, clear associations between TNBC and mutations in DNA-repair-related genes, especially BRCA-1 and BRCA-2 have been elucidated. These findings have subsequently guided therapeutic development. The early-stage setting has been the focus of much of this work, as it is clear that patients who have tumors that respond vigorously to chemotherapy preoperatively have a reduced likelihood of later metastatic recurrence compared to those who have poorly-responsive disease. Capitalizing on this knowledge, trials in the neoadjuvant setting have defined the importance of pathologic complete response (pCR) as a surrogate endpoint, and have shed light on differential effects of standard therapy (such as platinums), development of new targeted therapies (such as PARP inhibitors) and the role of immunotherapy. The high rate of observed recurrence in patients who have high stage disease at diagnosis, or, in particular, residual disease after neoadjuvant therapy, has also led to the launch of clinical trials in the adjuvant and post-neoadjvuant setting designed to specifically address micrometastatic minimal residual disease and therapy resistance. The advantage of the post-neoadjvuant approach to trials amongst patients with residual disease is to decrease the size of adjuvant trials, and allow them to be focused within populations most at risk of recurrence, sparing those with good prognosis the need for additional, potentially toxic treatment. Despite this progress, there are still many unanswered questions regarding optimal therapy and potential to improve outcomes in TNBC. This session will review the state of the science with regard to biology, new treatment approaches, and the value of both the neoadjuvant and post-neoadjvuant settings in developing optimal approaches to tailor therapy on the basis of risk stratification, reduce recurrence, and improve outcomes for women presenting with triple negative breast cancer. Citation Format: DeMichele A. Optimizing treatment of early stage triple negative breast cancer: Clinical challenges and new scientific horizons [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 ES9-1.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"36 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":"116283911","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 BS1-3: New insights into early-stage bone colonization of disseminated breast cancer cells","authors":"Xiang Zhang","doi":"10.1158/1538-7445.SABCS18-BS1-3","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-BS1-3","url":null,"abstract":"The fate of disseminated tumor cells is heavily influenced by their microenvironment niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using a variety of pre-clinical models and bioinformatics analyses of clinical data. We find that disseminated tumor cells may follow a “migration-by-tethering” mechanism to reach the osteogenic niche and establish tight direct interaction with the osteogenic cells. This interaction in turn profoundly alters signaling cascades in bone micrometastases. Heterotypic adherens junctions between cancer cells and osteogenic cells induce activation of the mTOR signaling. Gap junctions mediate calcium flux from osteogenic cells to cancer cells, and activate the calcium signaling. Upon the development of these junctions, ER signaling in ER+ breast cancer cells is dramatically suppressed, conferring endocrine independence. These alterations lead to unexpected therapeutic resistance and sensitivity, which were elucidated in part by a novel ex vivo bone-in-culture array system. Our findings, together with others in the literature, demonstrate the importance of considering microenvironment effects in metastatic therapies, and suggest novel therapeutic strategies to eliminate micrometastases. Citation Format: Zhang X. New insights into early-stage bone colonization of disseminated breast cancer cells [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 BS1-3.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"4 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":"128686408","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 ES10-2: Mining noncoding mutations for drivers of development in ER alpha-positive breast cancer","authors":"M. Lupien","doi":"10.1158/1538-7445.sabcs18-es10-2","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-es10-2","url":null,"abstract":"","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"47 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":"127213780","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 PL1: Breast Tumor Evolution and Intratumor Heterogeneity - Insights from Single Cell Genomics","authors":"N. Navin","doi":"10.1158/1538-7445.SABCS18-PL1","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-PL1","url":null,"abstract":"Breast tumors evolve from single cells in the ducts and acquire mutations leading to divergent lineages and intratumor heterogeneity in invasive cancers. To understand the genomic evolution of breast cancers during complex evolutionary processes including initiation, invasion and therapeutic resistance we have developed single cell sequencing (SCS) methods. I will discuss our efforts in applying SCS methods to study invasion in 10 premalignant breast cancer patients with ductal-carcinoma-in-situ (DCIS), which led to a discovery of early punctuated copy number evolution in the ducts and multi-clonal invasion. I will also discuss our work in applying both single cell DNA and RNA sequencing methods to study chemoresistance evolution in 20 triple-negative breast cancer patients using longitudinal samples, which identified an adaptive genomic evolution and acquired transcriptional reprogramming during resistance. Finally I will present unpublished work on our efforts to develop a 9Human Breast Cell Atlas9 of cell types and cell states (transcriptional programs) of normal cell types, and recent work on delineating copy number evolution in BRCA-positive breast cancer patients. Citation Format: Navin N. Breast Tumor Evolution and Intratumor Heterogeneity - Insights from Single Cell Genomics [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 PL1.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"22 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":"116751058","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 ES6-3: Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states","authors":"T. Graeber","doi":"10.1158/1538-7445.SABCS18-ES6-3","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-ES6-3","url":null,"abstract":"Targeted therapies have demonstrated clinically impactful efficacies. Upfront and adaptive tumor heterogeneity and plasticity present a next challenge to advancing cancer therapeutics further. We are using systems biology and integrative omic approaches towards identifying i) vulnerabilities of aggressive tumor types and ii) combination therapies for preventing resistance. We are incorporating functional datasets defining drug sensitivities (drug screens) and genetic vulnerabilities (shRNA knockdown and CRISPR knockout screens) to identify phenotype-associated cellular susceptibilities. In cancer cells highly dependent upon glucose for survival, we found that glucose withdrawal activates a positive feedback loop involving reactive oxygen species (ROS), ROS-mediated inhibition of tyrosine phosphatases, and tyrosine kinase signaling. This loop amplifies ROS to toxic levels, resulting in cell death. In a process that has parallels to the epithelial to mesenchyme transition (EMT), melanoma cells can undergo dedifferentiation. New standard of care therapies, such as kinase inhibition and immunotherapy, can promote dedifferentiation as a therapy escape route. We found that de-differentiated melanomas have increased sensitivity to ferroptosis - a cell death mechanism tied to metabolism and oxidized lipid membranes. Targeting ferroptosis in combination with standard therapies can block this dedifferentiation resistance escape route. Citation Format: Graeber T. Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states [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 ES6-3.","PeriodicalId":224797,"journal":{"name":"Invited Speaker Abstracts","volume":"262 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":"122900388","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}