General Session Abstracts最新文献

{"title":"Abstract GS4-07: Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial","authors":"K. Albain, R. Gray, J. Sparano, D. Makower, K. Pritchard, D. Hayes, C. Geyer, E. Dees, Mp Goetz, J. Olson, T. Lively, S. Badve, T. Saphner, Lindsay Wagner, T. Whelan, M. Ellis, S. Paik, W. Wood, P. Ravdin, M. Keane, H. Gómez, P. Reddy, T. Goggins, I. Mayer, A. Brufsky, D. Toppmeyer, V. Kaklamani, J. Berenberg, J. Abrams, G. Sledge","doi":"10.1158/1538-7445.SABCS18-GS4-07","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS4-07","url":null,"abstract":"Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (>2 cm vs. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age ( Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [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 GS4-07.","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75179446","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 GS4-04: Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer","authors":"F. Vicini, R. Cecchini, J. White, T. Julian, D. Arthur, R. Rabinovitch, R. Kuske, D. Parda, P. Ganz, M. Scheier, K. Winter, S. Paik, H. Kuerer, L. Vallow, L. Pierce, E. Mamounas, J. Costantino, H. Bear, I. Germaine, G. Gustafson, L. Grossheim, I. Petersen, R. Hudes, W. Curran, N. Wolmark","doi":"10.1158/1538-7445.SABCS18-GS4-04","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS4-04","url":null,"abstract":"Background: Conventional WBI after lumpectomy for early-stage breast cancer decreases ipsilateral breast tumor recurrence (IBTR), yielding comparable results to mastectomy. Accelerated PBI appears effective in reducing IBTR by treating only the tumor bed area. As the majority of IBTR occur at or in the vicinity of the tumor bed, we hypothesized that PBI would be as effective as WBI in controlling IBTR. The primary aim of NSABP B-39/RTOG 0413 was to determine if PBI provides equivalent local tumor control post lumpectomy compared to WBI in pts with early-stage breast cancer. The equivalency test was based on a 50% margin of increase in the hazard ratio (HR=1.5). Secondary endpoints included: overall survival (OS), recurrence-free interval (RFI), distant disease-free interval (DDFI), and toxicity. Methods: Eligible pts had lumpectomy with histologically-free margins and 0-3 positive axillary nodes. Pts were stratified by stage, menopausal status, hormone receptor status, and intent to receive chemotherapy and then randomized to PBI or WBI. PBI was 10 fractions of 3.4-3.85 Gy, given twice daily with either brachytherapy or 3D external beam radiation. WBI was 50 Gy in 2 Gy fractions given daily with a sequential boost to the surgical cavity. Follow-up was every 6 mos for 5 yrs and then annually. All analyses were by intent-to-treat. Results: From 3-21-05 to 4-16-13, 4216 pts were randomized: 2107 PBI; 2109 WBI. 61% were postmenopausal; 81% were hormone receptor-positive; 29% intended to receive chemotherapy. Stage distribution was: DCIS, 24%; invasive pN0, 65%; invasive pN1, 10%. As of 7-31-18, median follow-up was 10.2 yrs. There were 161 IBTRs as first events: 90 PBI v 71 WBI (HR 1.22; 90%CI 0.94-1.58). Per protocol-defined margin, to declare PBI and WBI equivalent regarding IBTR risk, the 90% CI for the observed HR had to lie entirely between 0.667 and 1.5. The percent of pts IBTR-free at 10 yrs was 95.2% PBI v 95.9% WBI. A statistically significant difference in the 10-yr RFI rate favored WBI (91.9% PBI v 93.4% WBI; HR 1.32; 95%CI 1.04-1.68; p=0.02). No statistically significant differences existed between PBI and WBI in DDFI (HR 1.31; 95%CI 0.91-1.91; p=0.15), OS (HR 1.10; 95%CI 0.90-1.35; p=0.35), or DFS (HR 1.12; 95%CI 0.98-1.29; p=0.11). Grade 3 toxicity was 9.6% PBI v 7.1% WBI, and grade 4-5 toxicity was 0.5% v 0.3%, respectively. Discussion: PBI did not meet the criteria for equivalence to WBI in controlling IBTR based on the upper limit of the hazard ratio confidence interval. However, the absolute difference in 10-yr rate of IBTR was Support: U10CA180868, -180822, UG1CA189867. Citation Format: Vicini FA, Cecchini RS, White JR, Julian TB, Arthur DW, Rabinovitch RA, Kuske RR, Parda DS, Ganz PA, Scheier MF, Winter KA, Paik S, Kuerer HM, Vallow LA, Pierce LJ, Mamounas EP, Costantino JP, Bear HD, Germaine I, Gustafson G, Grossheim L, Petersen IA, Hudes RS, Curran, Jr. WJ, Wolmark N. Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A ran","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81780357","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 GS3-05: Prospective optimization of estrogen receptor degradation yields ER ligands with variable capacities for ER transcriptional suppression","authors":"Ciara Metcalfe, Wei Zhou, Jane Guan, A. Daemen, M. Hafner, R. Blake, E. Ingalla, Amy E. Young, J. Oeh, T. Bruyn, S. Ubhayakar, I. Chen, J. Giltnane, Jun Li, Xiaojing Wang, D. Sampath, J. Hager, L. Friedman","doi":"10.1158/1538-7445.SABCS18-GS3-05","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS3-05","url":null,"abstract":"ER+ breast cancers can depend on ER signaling throughout disease progression, including after acquired resistance to existing endocrine agents, providing a rationale for further optimization and development of ER-targeting agents. Fulvestrant is unique amongst currently approved ER ligand therapeutics due to classification as a full ER antagonist, which is thought to be achieved through degradation of ER protein. However, the full clinical potential of fulvestrant is believed to be limited by poor bioavailability, spurring attempts to generate ligands capable of driving ER degradation but with improved drug-like properties. Here, we evaluate three ER ligand clinical candidates that recently emerged from prospective optimization of ER degradation – GDC-0810, AZD9496 and GDC-0927 - and show that they display distinct mechanistic features. GDC-0810 and AZD9496 are more limited in their ER degradation capacity relative to GDC-0927 and fulvestrant, display evidence of weak transcriptional activation of ER in breast cancer cells (i.e. partial agonist activity), and do not achieve the same degree of in vitro anti-proliferative activity as GDC-0927 and fulvestrant. In the HCI-013 (ER.Y537S) and HCI-011 (ER.WT) ER+ patient-derived xenograft models, GDC-0927 drives greater transcriptional suppression of ER, and greater anti-tumor activity relative to GDC-0810. We found that despite their full antagonist phenotype, GDC-0927 and fulvestrant promote association of ER with DNA, including at canonical ERE motifs, prior to ER degradation. Interestingly however, integration of ER ChIP-Seq and ATAC-Seq data revealed that ER complexed with fulvestrant or GDC-0927 fails to increase chromatin accessibility at DNA binding sites, in contrast to partial agonists which result in increased chromatin accessibility at ER binding sites. Thus, although ER contacts DNA when engaged with fulvestrant and GDC-0927, it is functionally inert. To further explore mechanistic features that might account for the differential activity of full antagonists and partial agonists that occurs prior to ER degradation, we used cell-based florescence recovery after photobleaching (FRAP) to measure the kinetics of ER diffusion within the nucleus. We demonstrate that while ER is generally highly mobile, including after engagement with GDC-0810 and AZD9496, GDC-0927 and fulvestrant immobilize intra-nuclear ER. A site saturating mutagenesis screen revealed a series of novel ER mutations that prevent ER immobilization by fulvestrant and GDC-0927. This class of “always mobile” ER variants promotes an antagonist-to-agonist transcriptional switch for fulvestrant and GDC-0927, and simultaneously prevents ER degradation by these molecules, implying that ER immobilization is a key functional determinant of robust transcriptional suppression. We thus propose that ER degradation is not a driver of full ER antagonism, but rather a downstream consequence of ER immobilization, occurring after a suppressive phen","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"31 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82017929","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 GS2-05: Impact of the delayed initiation of adjuvant chemotherapy in the outcomes of triple negative breast cancer","authors":"Z. Morante, R. Ruiz, G. Ku, F. Namuche, R. Mantilla, M. Luján, H. Fuentes, J. Schwarz, A. Aguilar, S. Neciosup, H. Gómez","doi":"10.1158/1538-7445.SABCS18-GS2-05","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS2-05","url":null,"abstract":"Background: Adjuvant chemotherapy decreases the risk of recurrence and improves survival rates but it is unclear whether a delayed initiation is associated with adverse outcomes. Information available is especially scarce for triple negative breast cancer (TNBC) which represents a high-risk group. We evaluated the influence of time to chemotherapy (TTC) on TNBC patient9s survival outcomes. Methods: We retrospectively analyzed the data using the medical records of TNBC patients who received adjuvant chemotherapy at Instituto Nacional de Enfermedades Neoplasicas between 2000-2014. TTC was defined as the number of days between surgery and the first dose of chemotherapy. Patients were categorized into 4 groups according to TTC: ≤30, 31-60, 61-90, ≥91 days. We evaluated recurrence-free survival (RFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used. Results: 687 patients were included. Mean age at diagnosis was 49.15 (range, 21-89) and most patients were stage II (60.1%) or III (29.45%). They received either anthracyclines or anthracyclines and taxane-based chemotherapy (96.1%). Median TTC was 41 days. 189 (27.5%) received chemotherapy at or before 30 days; 329 (47.9%), between 31 and 60 days; 115 (16.7%), between 61 and 90 days and; 54 (7.9%) beyond 90 days. Median follow-up was 101 months. 10y-DFS was 81.4%, 68.6%, 70.8% and 68.1% among patients who received chemotherapy ≤30, 31-60, 61-90, ≥91 days, respectively (p=0.005). Accordingly, 10y-OS was 82%, 67.4%, 67.1% and 65.1% among patients who received chemotherapy ≤30, 31-60, 61-90, ≥91 days, respectively (p=0.003). In the multivariate analysis, TTC was an independent prognostic factor for RFS and OS. Patients with TTC of 31-60 days (HR, 1.92; 95% CI, 1.225 to 2.998), 61-90 days (HR, 2.38; 95% CI, 1.354 to 4.172) and ≥91days (HR, 2.47; 95% CI, 1.250 to 4.886); had worse survival compared with those who initiated treatment in the first 30 days after surgery. Patients with TTC of 31-60 days (HR, 1.94; 95% CI, 1.243 to 3.034), 61-90 days (HR, 2.45; 95% CI, 1.402 to 4.265) and ≥91days (HR, 2.79; 95% CI, 1.418 to 5.506); had worse survival compared with those who initiated treatment in the first 30 days after surgery. Conclusion: Delayed initiation of adjuvant chemotherapy in TNBC patients over 30 days is associated with a decrease in RFS and OS rates. The greater the delay, the worse the outcomes. As this represents a feasible opportunity for improvement, every attempt should be made to avoid delayed adjuvant chemotherapy initiation in this high-risk group of patients. Citation Format: Morante Z, Ruiz R, De la Cruz - Ku G, Namuche F, Mantilla R, Lujan MG, Fuentes H, Schwarz J, Aguilar A, Neciosup S, Gomez H. Impact of the delayed initiation of adjuvant chemotherapy in the outcomes of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;7","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74862543","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 GS3-08: Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial","authors":"D. Juric, E. Ciruelos, G. Rubovszky, M. Campone, S. Loibl, H. Rugo, H. Iwata, P. Conte, I. Mayer, B. Kaufman, T. Yamashita, Y. Lu, Kenichi Inoue, M. Takahashi, Z. Pápai, A. Longin, D. Mills, C. Wilke, D. Sellami, F. André","doi":"10.1158/1538-7445.SABCS18-GS3-08","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS3-08","url":null,"abstract":"Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose >250mg/dL; 37% for ALP+FUL vs Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast can","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89913332","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 GS1-03: Crosstalk between osteoblasts and breast cancer cells alters breast cancer proliferation through multiple mechanisms","authors":"K. Bussard, A. Shupp, Alexus D Kolb, D. Mukhopdhyay","doi":"10.1158/1538-7445.SABCS18-GS1-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS1-03","url":null,"abstract":"BrCa preferentially metastasizes to bone, where the 5-year relative survival rate is In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Osteoclasts excavate erosion cavities and osteoblasts (OB) synthesize bone matrix, with no net bone gain or loss. However, when metastatic BCC invade bone, this balance is disrupted to favor bone loss. Bisphosphonate treatments are not curative. OBs do not deposit new bone. This result suggests that OBs may be altered or experience a loss-of-function in the tumor niche. We have new, late-breaking evidence to suggest that communication between OBs and BCCs 9educates9 OBs to produce factors that suppress BCC proliferation in bone. We have in-vitro and in-vivo mouse-model evidence that 9educated9 osteoblasts (EOs) have a unique secretory protein profile compared to 9uneducated9 OBs. We also identified EOs as being present in the bone tissue samples of human patients with bone metastatic BrCa via multi-plex immunofluorescence. When we treated BCCs with EO conditioned media (CM), BCC proliferation was reduced in both triple negative and ER+ metastatic BCCs, while CM from 9uneducated9 OBs did not affect BCC proliferation. This effect was mediated through alterations in EO production of decorin and NOV. We identified EO CM as a rich source of exosomes (exo) and confirmed the presence of an exo population via iodixanol density gradient and western blotting for specific exo protein markers. We found that EO-derived exo, but not 9uneducated9 OB-derived exo, decreased proliferation of ER+ and triple negative BCC. Also, treatment with EO-derived exosomes increased the number of Ki67 negative metastatic BCC. Moreover, we labeled EO exo with RFP-conjugated CD63 to visually confirm exo transfer from EO cells to BCCs using confocal microscopy. And, co-culture with EOs increased triple negative and ER+ metastatic BrCa expression of p21 compared to co-cultures with 9uneducated9 OBs. Our data suggest that EOs use multiple mechanisms of cellular communication to regulate BCC proliferation in bone. Impact: Our late-breaking data suggest that OBs produce factors that suppress metastatic BCC growth. Much less attention has been given to OB interactions with tumor cells at sites of bone metastasis due to observations that OB populations are reduced at sites of advanced osteolysis. However, we propose that OBs may be valuable endogenous targets to aid in restoration of bone deposition and suppression of metastatic BrCa growth in the niche in concert with therapeutic drugs to kill the cancer cells. Our data suggest there is a population of OBs that demonstrate a functional role in retarding metastatic BCC growth; a property capable of exploitation. Moreover, restoration of the OBs9 ability to deposit new bone would lead to better quality of life and increased time of survival for bone metastatic BrCa patients where bone loss is found. For these reasons, OBs and EOs are suitable candidates for therap","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74793670","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 GS6-02: A randomized, double-blind, placebo-controlled trial of oxybutynin (Oxy) for hot flashes (HF): ACCRU study SC-1603","authors":"R. Leon-Ferre, P. Novotny, S. Faubion, K. Ruddy, D. Flora, C. Dakhil, K. Rowland, M. Graham, N. Le-Lindqwister, C. Loprinzi","doi":"10.1158/1538-7445.SABCS18-GS6-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS6-02","url":null,"abstract":"Background: HF occur in about 75% of midlife women and are associated with quality of life disruption and premature endocrine therapy discontinuation among breast cancer survivors. Estrogen therapy, effective for HF, is contraindicated in hormone receptor-positive breast cancer (BC). Previous studies have suggested that Oxy could be effective in managing HF. Methods: This randomized, placebo (P)-controlled trial enrolled women who had experienced HF ≥28 times per week over >30 days and of sufficient severity to seek treatment. Patients (pts) were randomized to receive oral Oxy at two doses: 2.5mg BID for 6 weeks (Oxy2.5), 2.5mg BID for a week with subsequent increase to 5mg BID (Oxy5), or matching P, in equal ratios. Baseline and monthly questionnaires were administered including a HF diary, the HF related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in weekly HF score and frequency from baseline to end of study compared using Kruskal-Wallis tests. Results: 150 pts were accrued between 2/23/2017-3/5/2018. 4 pts cancelled before starting treatment and were excluded from analyses. This interim report includes the first 104 pts for which at least one post-baseline evaluation was available. Baseline characteristics were well-balanced between the arms. Sixty-two percent were on tamoxifen or an aromatase inhibitor for the duration of the study. Pts on both Oxy doses had a significantly greater reduction in HF score and frequency compared to P. Pts on Oxy2.5 had a mean change in HF score of -10 (SD 7.4) vs -5.1 (SD 9.7) with P, p=0.003; and a mean change in average weekly number of HF of -4.6 (SD 3.1) vs -2.3 (SD 3.9), p=0.002. Pts on Oxy5 had a mean change in HF score of -16.2 (SD 5.1) vs -5.1 (SD 9.7) with P, p Conclusions: Oxy is superior to P for management of HF. Oxy2.5 and 5 were both associated with significant improvements in HF scores and frequency as well as improvement in HF interference with several quality of life measures. While pts on Oxy experienced more side effects than pts on P, rates of discontinuation due to adverse events were low. This study was supported by the Breast Cancer Research Foundation. Citation Format: Leon-Ferre RA, Novotny PJ, Faubion SS, Ruddy KJ, Flora D, Dakhil C, Rowland KM, Graham ML, Le-Lindqwister N, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of oxybutynin (Oxy) for hot flashes (HF): ACCRU study SC-1603 [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 GS6-02.","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76902113","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 GS5-01: A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab","authors":"P. Munster, J. Krischer, R. Tamura, A. Fink, L. Bello-Matricaria, M. Guilin","doi":"10.1158/1538-7445.SABCS18-GS5-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS5-01","url":null,"abstract":"Background: Exposure to trastuzumab for one year is an integral part of therapy for patients with early stage HER2-positive breast cancer. Yet, cardiac side effects, particularly in patients who also receive anthracyclines require frequent monitoring and result in dose interruptions and discontinuation of trastuzumab. Prophylactic use of angiotensin converting enzyme (ACE) nhibitors or beta blockers (BB) may prevent cardiotoxicity associated with chemotherapy and trastuzumab. Methods A large community-based prospective double-blind, placebo-controlled trial, evaluated the rates of pre-specified cardiotoxicity in patients with early stage breast cancer treated with one year of trastuzumab. Cardiac events were followed for two years. Patients were randomized to simultaneously receive either the ACE inhibitor, lisinopril, or the BB, carvedilol, or placebo and were further stratified by anthracycline use to determine whether ACE inhibitors or BB can prevent trastuzumab-induced decrease in left ventricular ejection fraction (LVEF) and trastuzumab interruptions. Results: The study included 468 eligible patients (median age:51, BMI:27 kg/m 2 , baseline systolic BP: 126mmHg and LVEF :63 ± 6.29%) from 127 community-based practices, 189 patients received an anthracycline. For the entire study population and the non-anthracycline group, no difference in number of trastuzumab interruptions were seen. For patients receiving an anthracycline, cardiac event rates were higher in the placebo group (47%), and reduced in both the lisinopril (37%), and the carvedilol (31%) groups. Interruptions of trastuzumab were required in 23% patients on lisinopril and 20% on carvedilol compared to 40% on placebo (p=0.007). Changes in LVEF from baseline (least square means, SE) were significantly reduced with both carvedilol (-4.5 (0.8), p=0.008, and lisinopril (-4.0 (0.8), p=0.002) than placebo, (-7.7 (0.8). Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio 0.49, 95% confidence intervals 0.27, 0.89, p=0.009) or lisinopril (HR 0.53, CI 0.30, 0.94, p=0.015). Conclusions In patients with HER2-positive breast cancer receiving trastuzumab and an anthracycline, both lisinopril and carvedilol during treatment reduced cardiotoxicity in patients, but not in those with non-anthracyline containing regimens. The use of lisinopril or carvedilol may allow the use of an anthracycline without compromising trastuzumab treatment in those who might benefit from an anthracycline. Citation Format: Munster P, Krischer J, Tamura R, Fink A, Bello-Matricaria L, Guilin M. A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab [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):Abstrac","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73629625","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 GS3-02: PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib","authors":"M. Dowsett, S. Jacobs, S. Johnston, J. Bliss, D. Wheatley, Christopher Holcombe, R. Stein, S. McIntosh, P. Barry, D. Dolling, C. Snowdon, S. Perry, Leona M. Batten, A. Dodson, Vera Martins, A. Modi, C. Cornman, S. Puhalla, N. Wolmark, T. Julian, K. Pogue-Geile, A. Robidoux, L. Provencher, J. Boileau, I. Shalaby, M. Thirlwell, K. Fisher, C. H. Bartlett, M. Koehler, K. Osborne, M. Rimawi","doi":"10.1158/1538-7445.SABCS18-GS3-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS3-02","url":null,"abstract":"Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial collaboration between UK and NSABP investigators evaluating the biological and clinical effects of palbociclib with letrozole combination as neoadjuvant therapy. Methods: Postmenopausal women with ER+ primary breast cancer and tumors >2.0cm (ultrasound) were randomized to one of 4 treatment groups (3:2:2:2 ratio): Group A: letrozole (2.5mg/d) for 14 weeks; Group B: letrozole for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group C: palbociclib for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group D: letrozole + palbociclib for 14 weeks. Palbociclib was given 125mg/d PO on a 21 days on, 7 days off schedule. Post-14 week treatment was at the discretion of the treating clinician including letrozole until surgery. Core-cut biopsies were taken at baseline, 2 weeks and 14 weeks. Co-primary endpoints for letrozole alone vs palbociclib groups (Group A vs Groups B+C+D) were: (i) change in Ki67 (IHC) between baseline and 14 weeks (log-fold change, Mann-Whitney test); (ii) clinical response (ultrasound) after 14 weeks (4 group, ordinal, Mann-Whitney test). Complete cell-cycle arrest (CCCA) (Ki67≤2.7%) was analyzed using a logistic regression model adjusting for recruitment region. Pre-specified exploratory biomarkers included c-PARP (apoptosis). Results: 307 patients were recruited between 27 Feb 2015 and 08 Mar 2018; 103 were randomized to letrozole alone and 204 to letrozole + palbociclib. 279 (90.9%) patients were evaluable for 14 week clinical response. Clinical response was not significantly different between letrozole vs letrozole + palbociclib groups [(p=0.20; CR+PR 49.5% (46/93) vs 54.3% (101/186) and PD 5.4% (5/93) vs 3.2% (6/186)] nor was the small proportion of patients with pathological CR (1/87, 1.1% vs 6/180, 3.3%; p=0.43). 190 (61.9%) patients were evaluable for 14 week change in Ki67. The median log-fold change in Ki67 was greater with letrozole + palbociclib vs letrozole alone (-4.1 vs -2.2; p Conclusion: Adding palbociclib to letrozole markedly enhanced the suppression of malignant cell proliferation as assessed by Ki67 but did not substantially increase the clinical response of primary ER+ breast cancer over a 14-week period. Concurrent reductions in cell death may have reduced the speed of tumor shrinkage. Citation Format: Dowsett M, Jacobs S, Johnston S, Bliss J, Wheatley D, Holcombe C, Stein R, McIntosh S, Barry P, Dolling D, Snowdon C, Perry S, Batten L, Dodson A, Martins V, Modi A, Cornman C, Puhalla S, Wolmark N, Julian T, Pogue-Geile K, Robidoux A, Provencher L, Boileau JF, Shalaby I, Thirlwell M, Fisher K, Huang Bartlett C, Koehler M, Osborne K, Rimawi M. PALLET: A ","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74670066","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 GS2-01: Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study","authors":"F. Couch, Chunling Hu, S. Hart, Rohan D Gnanaolivu, J. Lilyquist, Ky Lee, Chi Gao, B. Eckloff, R. Samara, J. Klebba, P. Auer, L. Bernstein, M. Gaudet, C. Haiman, J. Palmer, S. Yao, S. Domchek, J. Weitzel, D. Goldgar, K. Nathanson, P. Kraft, E. Polley","doi":"10.1158/1538-7445.SABCS18-GS2-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-GS2-01","url":null,"abstract":"Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)>4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the >50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM,CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection o","PeriodicalId":12697,"journal":{"name":"General Session Abstracts","volume":"12 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83363181","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}