bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-06-02: Androgen receptor signaling regulates survival to ionizing radiation in breast cancers
Authors: Yard BD , Abazeed ME
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P5-06-03: A solution to the APOBEC mutation paradox in breast cancer
Authors: Harris RS , Starrett GJ , McCann JL , Carpenter MA
Published: March 2017

Breast cancer has a major genetic component, and individual tumors can have thousands to tens-of-thousands of mutations. Large proportions are cytosine mutations in TCA and TCT trinucleotide motifs. A variety of studies have attributed this mutation signature to the APOBEC family of DNA cytosine deaminases, with previous literature favoring APOBEC3B as the most likely enzyme to bee responsible (from a total of nine active family members). However, breast tumor genomic DNA sequences from patients with a naturally occurring germline deletion of the entire APOBEC3B gene still show an intact APOBEC mutation signature.

To resolve this paradox, we tested the hypothesis that the only other functionally dimorphic APOBEC family member, APOBEC3H, may be responsible. First, we performed an unbiased genetic analysis of TCGA data sets and showed that APOBEC3B-null tumors with this mutational bias have at least one copy of the haplotype-I variant of APOBEC3H, despite weak genetic linkage between these two genes (n=14/14). Remarkably, breast tumors without APOBEC3B and APOBEC3H haplotype-I showed no evidence for an APOBEC mutation signature (n=3/3). The proportion of APOBEC signature mutations between the cohort with and the cohort without APOBEC3H haplotype-I was highly significant (p<0.00001 and lower), indicating that these two enzymes alone may be fully responsible (and casting serious doubt on the potential role of APOBEC3A). Second, although deemed inactive in prior studies, we discovered that APOBEC3H haplotype-I has robust activity in biochemical assays with mutation of TCA-containing single-stranded DNA and in cellular assays with hypermutation of HIV-1 cDNA and mutation of a genomic DNA eGFP reporter gene. Third, the subcellular localization APOBEC3H haplotype-I and other expressed variants of this enzyme differed with only the latter showing significant nuclear localization in a panel of cell lines. The genomic mutagenicity and localization of APOBEC3H haplotype-I is attributable to a glycine at position 105, whereas other variants of this enzyme that have an arginine at this position, suggesting a general molecular mechanism. These studies combine to offer a parsimonious solution to the APOBEC mutation paradox with APOBEC3B and APOBEC3H haplotype-I, together, accounting for the strong “APOBEC mutation signature” observed in many breast cancers.

Citation Format: Harris RS, Starrett GJ, McCann JL, Carpenter MA. A solution to the APOBEC mutation paradox in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-03.
Abstract P5-06-05: Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers
Authors: Boucher D , Newsome D , Takemoto D , Hillier S , Wang Y , Arimoto R , Maxwell J , Charifson P , Fields SZ , Tanner K , Penney MS
Published: March 2017

Background: The efficacy of chemotherapeutic agents such as doxorubicin, which cause lethal DNA double-strand breaks (DSBs), is diminished by efficient repair of the damaged DNA in cancer cells. DNA-PK is a key regulator of the non-homologous end joining (NHEJ) pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with doxorubicin both in vitro and in vivo.

Methods: VX-984 was examined as a single agent and in combination with doxorubicin or pegylated liposomal doxorubicin (PLD) in a panel of breast cancer cell lines and in mouse xenograft models, respectively.

Results: In vitro, inhibition of DNA-PK by VX-984 enhanced the cytotoxic activity of doxorubicin in established breast cancer cell lines and in primary ovarian tumor explants. Notably, mean Bliss DE >10% (strong synergy) were observed for doxorubicin in the presence of VX-984 in 22 of 35 breast cancer cell lines and 21 of 44 ovarian cancer cell lines in a broad cancer cell line screen. Further, the efficacy observed with VX-984 was associated with increased DNA damage as measured by phosphorylated histone H2AX (gamma-H2AX) and phosphorylated Kruppel-associated protein (pKAP1) in DU4475, MDA-MB-436 and MDA-MB-468 breast cancer cell lines, which is consistent with diminished DSB repair. In vivo, VX-984 significantly enhanced the efficacy of PLD in ovarian cancer patient-derived xenograft models and in cell line xenograft models.

Conclusions: These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of doxorubicin in preclinical models and support the use of VX-984 in combination with DSB agents such as anthracyclines including PLD for the treatment of breast and ovarian cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD.

Sponsored by Vertex Pharmaceuticals Incorporated.

Citation Format: Boucher D, Newsome D, Takemoto D, Hillier S, Wang Y, Arimoto R, Maxwell J, Charifson P, Fields SZ, Tanner K, Penney MS. Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-05.
Abstract P5-06-06: Comprehensive analysis of the DNA damage repair and maintenance pathways that regulate TNBC sensitivity to replication stress
Authors: Redwood AB , Cai S , Jeter-Jones S , Tu Y , Piwnica-Worms H
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-08-05: Prospective family cohort analyses of gene-environment interactions in breast cancer: Body mass index
Authors: Terry MB , Dite GS , Phillips K-A , Andrulis IL , John EM , Daly MB , Buys SS , Hopper JL
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-08-29: Trends in age shifting and decreasing mortality of female breast cancer in Taiwan with emerging molecular subset of unmet medical need: A 30-year cohort observation from Taipei Veterans General Hospital
Authors: Lin Y-S , Tseng L-M , Liu C-Y
Published: March 2017

Background: Over the past thirty years, Taiwan has become a modern Asian country with an increasing incidence of breast cancer. We hypothesized that the epidemiological and demographic features of breast cancer patients in Taiwan have changed by using cohort study based on data collected from past three decades. However, despite improvement in prognosis of most breast cancer subtypes, we found that one subtype of luminal B type her-2 negative did not show significant improvement in overall survival and disease free survival from our cohort comparison.

Methods:Patients with primary breast cancer diagnosed between 1979 and 2010 were identified from the cancer registry database at Taipei Veterans General Hospital, Taiwan. Three periods of time were divided (1979 to 1988, 1989 to 1998, and 1999 to 2010) and compared to determine the epidemiological changes in female breast cancer in Taiwan.

Results:From 1979 to 2010, data from a total of 8417 breast cancer patients were collected. The ratio of breast cancer patients aged ≤ 35 years decreased from 13.3% in 1979 to 1988, to 10.6% in 1989 to 1998, and to 5.2% during 1999 to 2010.In the period of 1979 to 1988, 55.7% of patients were aged ≤ 50 years, and in the period of 1999-2010, only 45.7% of breast cancer patients were aged ≤ 50 yrs.From 1979-1988, ductal carcinoma in situ (DCIS) was rarely diagnosed (0.2%), and the ratio of patients who initially presented with DCIS increased to 2.9% in 1989 to 1998, and to 11.8% in 1999 to 2010. Patients diagnosed with stage I breast cancer also increased from 16.7% in 1979-1988 to 28.4% in 1999-2010.Patients diagnosed and treated in 1999-2010 (5-year overall survival: 81.7%) had a much better outcome than patients treated in 1979-1988 (5-year overall survival: 66.3%). Cohort comparison of survival outcome for breast cancer subtypes in luminal A type, luminal B type Her-2 positive, luminal B type Her-2 negative, Her-2 type, and triple negative type disclosed no improvement in both 5-year survival and 5-year disease free survival outcomes in the subtype of luminal B type Her-2 negative.

Conclusions: The epidemiological features of female breast cancer in Taiwan have changed over the past thirty years. A molecular subtype of luminal B type Her-2 negative was characterized as an emerging group with unmet medical need.

Citation Format: Lin Y-S, Tseng L-M, Liu C-Y. Trends in age shifting and decreasing mortality of female breast cancer in Taiwan with emerging molecular subset of unmet medical need: A 30-year cohort observation from Taipei Veterans General Hospital [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-29.
Abstract P5-08-30: Utilization of oncotype DX for breast cancer in different facility types in Louisiana
Authors: Loch M , Li X , Mumphrey B , Garcia A , Wu X-C
Published: March 2017

Background: Oncotype DX, a 21-gene recurrence score, is the most validated prognostic assay that may identify both women most and least likely to benefit from adjuvant chemotherapy. It was added to the ASCO guidelines in 2007 and the NCCN guidelines in 2008 for use in node negative, hormone receptor (HR)+, HER2- breast cancer patients who will undergo 5 years of endocrine therapy. We explored its utilization in different cancer care settings to assess differences in the tool's utilization.

Methods: We analyzed data from the Louisiana Tumor Registry, one of the NCI funded SEER registries for cases of HR+ HER2- localized breast cancer from 2010-2012 and explored differences in utilization of the Oncotype DX by facility type – teaching hospital cancer program (THCP), community hospital comprehensive cancer program (COMP), community hospital cancer program (CHCP), commission on cancer program (COC) and public hospital program. Chemotherapy administration data was collected on the 2011 cases with chemotherapy data collected from a CDC funded special project Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER). Hospital sites were identified by the location where patients underwent surgery. Demographic and clinical factors were adjusted for using multivariate logistic regression.

Results: Of the patients who did have the Oncotype DX, 39.2% were white, 32.3% black. Women over 70 were much less likely (29.3% vs. >45% in women <70) to have the test. Patients who received surgery at public hospitals had the lowest chance (16.7%), whereas those who received surgery at COMP were most likely to have the test (43.1%) and at teaching hospitals, 31.8% had the test. The odds of not using Oncotype DX were significantly higher in public hospitals than THCP even after adjusting for demographic and clinical factors (OR=2.44; 95% CI: 1.39-4.27).

Odds Ratios and 95% CIs for Oncotype DX (No/Yes) in HR+/HER2- localized breast cancer in 2010-2012, LouisianaHospital type#Crude Odds Ratio and 95% CIAdjusted Odds Ratio and 95% CITHCP422referencereferenceCOMP4891.63 (1.24-2.14)0.56 (0.41-0.76)CHCP8101.35 (1.06-1.74)0.74 (0.56-0.98)Public1140.43 (0.25-0.73)2.44 (1.39-4.27)NonCOC/Non Public10321.37 (1.07-1.74)0.70 (0.53-0.92)

Conclusions: Patients who had the Oncotype DX performed in our Louisiana database were most likely white, <70 and had their surgeries at COMP. The odds of not having the Oncotype DX performed were significantly higher in public hospitals as compared with teaching hospitals when adjusting for demographic and clinical factors.

Citation Format: Loch M, Li X, Mumphrey B, Garcia A, Wu X-C. Utilization of oncotype DX for breast cancer in different facility types in Louisiana [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-30.
Abstract P5-08-31: Triple negative breast cancer and factors associated with its treatment in the US – A population study using central cancer registry data
Authors: Wu M , Thompson T , Ryerson B , Miller J , Singh S
Published: March 2017

This abstract was not presented at the symposium.
Abstract P5-09-01: Plasma osteoprotegerin and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
Authors: Kotsopoulos J , Oden L , Akbari M , Singer C , Sun P , Salmena L , Narod S
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P5-10-04: Spectrum of hereditary breast and ovarian cancer gene variants in an African American cohort
Authors: Shah PD , Digiovanni L , Maxwell KN , Bradbury AR , Van Den Akker J , Kim S , Gil E , Simon MS , Nathanson KL , Domchek SM
Published: March 2017

Background: Few reports describe the spectrum of mutations in breast and ovarian cancer predisposition genes found specifically in African Americans. Methods: 560 women who self-identified as African American (AA) from the University of Pennsylvania and Wayne State University were included in this IRB-approved, case-control study. Cases (n=218 with a personal history of breast and/or ovarian cancer) and controls (n=342 without breast or ovarian cancer) underwent germline genetic testing using the Color Genomics 19-gene breast and ovarian cancer risk panel. The subset of AA patients diagnosed with breast cancer ≤40 (n=185) was compared to an institutional cohort of white patients with breast cancer diagnosed ≤40 (n=189). Results: Of 218 AA cases, 70 had pathogenic or likely pathogenic (P/LP) mutations (BRCA1: n=36; BRCA2: n=24; TP53: n=3; RAD51D: n=2; ATM: n=2; CHEK2: n=2 and MSH6: n=1). Forty-two of 218 patients (19%) had at least one variant of uncertain significance (VUS). Of 342 AA controls, 5 women had P mutations in 5 distinct genes: BRCA2, ATM, BRIP1, PALB2 and PMS2. 55 control patients (16%) had at least one VUS. Many of the 75 P/LP mutations (cases, 70 mutations; controls, 5 mutations) in the full AA cohort were unique variants. In the 135 patients who had BRCA1/BRCA2 sequencing prior to testing under this protocol, the Color Genomics platform identified all 56 pathogenic mutations. Among AA patients diagnosed with breast cancer ≤40 (n=185), the incidence of TP53 and ATM pathogenic mutations was similar to the white, early-onset breast cancer cohort (n=189): TP53, 1% in both cohorts; ATM = 1% in AA patients and 2% in whites. However, no patients in the AA, early-onset cohort had germline CHEK2 mutations, compared to 4% of white, early-onset breast cancer patients (p=0.007). Conclusions: Taken together, the results of this study demonstrate the importance of considering germline mutation testing in the AA population. Examination of mutations and disease phenotypes within the AA population may facilitate understanding of the clinical risk associated with variants of uncertain significance. Further comparative data between the AA and white cohorts will be presented.

Citation Format: Shah PD, Digiovanni L, Maxwell KN, Bradbury AR, Van Den Akker J, Kim S, Gil E, Simon MS, Nathanson KL, Domchek SM. Spectrum of hereditary breast and ovarian cancer gene variants in an African American cohort [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-04.
Abstract P5-10-10: Predictors of breast density among Black and Hispanic women presenting for mammographic screening
Authors: Oppong BA , Dash C , Li Y , Makambi K , Coleman T , Adams-Campbell L
Published: March 2017

Background: Increased breast density has been associated with elevated breast cancer risk and complicating mammographic interpretation. Although previous studies have investigated population variations in breast density, Black and Hispanic women are often underrepresented in these analyses. Moreover, it is unclear how breast density differs between these ethnicities. We report on the mammographic density distribution of Black and Hispanic women having breast cancer screening at the Capital Breast Care Center (CBCC) and analyze factors associated with high breast density.

Methods: Retrospective data from electronic medical records at a population-based mammography screening center were abstracted. From 2010 to 2014, data from women undergoing their first breast cancer screening were reviewed. Patient demographics including race, age at screening, education and menopausal status were abstracted in addition to body mass index (BMI) and Breast Imaging-Reporting and Data System (BI-RADS) density category:1- “fatty”, 2- “scattered fibroglandular densities”, 3- “heterogeneously dense” and 4- “extremely dense”. Logistic regression was used to investigate factors associated with breast density.

Results: Density categorization was recorded for 1747 women over the five-year period, with 855 (49%) Black and 892 (51%) Hispanic. Patient characteristics associated with high density (categories 3 and 4) were younger age, Hispanic ethnicity, nulliparity, premenopausal status, and BMI < 30 kg/m2. On multivariate logistic regression, Hispanic ethnicity, premenopausal status, and BMI < 30 kg/m2 were predictive of high mammographic density.

Conclusion: In a sample of women presenting for mammographic screening at CBCC, Hispanic women were more likely to have higher breast density compared to Black women. After controlling for ethnicity, postmenopausal and obese women were less likely to have dense breasts. Additional investigation is needed to further study the impact of obesity on breast density in underserved minority women.

Citation Format: Oppong BA, Dash C, Li Y, Makambi K, Coleman T, Adams-Campbell L. Predictors of breast density among Black and Hispanic women presenting for mammographic screening [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-10.
Abstract P5-11-13: Experience in the ABC Medical Center of Mexico City 2010-2015 using scalp-cooling system (DigniCap) for prevention of alopecia induced by chemotherapy
Authors: Hernandez RE , Gerson R , Olivares G , Rivera S , Serrano A , Villalobos A , Lazaro M
Published: March 2017

Background: Alopecia is one of the secondary side effect whit the most emotionally impact for patients undergoing chemotherapy (CTX) The DigniCap System is the first scalp cooling system use to minimize alopecia. Methods: The objetive of this study was to evaluate in a restrospective trial the efficacy of DigniCap preventing alopecia in consecutive patients treated in ABC Medical Center from December 2010 to January 2015. Patients recieve different chemotherapy regimens, with different modalities, neo , adyuvant and for metastases in first and second line, as in many clinical stages whit breast cancer (BC), were evaluated with the visual scale of Dean (score 0: 0-25%, 1: 25-50%, 2: 50-75%, 3: 75-100%) with photographs of the before and after treatment. Results: 120 pts with BC in stages I-V were treated with a taxane and antraciclins regimen of chemotherapy, 66 pts receive 12 treatment weekly of paclitaxe (T)l and 4 adriamicin/cyclophosphamida (AC) every 21 days, 28 pts 6-8 cycles every 21 days AC-Taxol, 22 pts (18%)suspended the treatment because of the loss of more than 50% of hair at the 2nd an 3rd chemotherapy cycle. 98 pts actually finished the treatment (72%). Of these, 82 pts (84%) no had or had a minimal loss of hair (Dean score 0-1), 16 pts (16%) had a 50% of hair loss (Dean score 3). 8pts recieve more than one regimen of chemotherapy. In the tracing any metastases or side effects were presented with the use of DigniCap. Conclusions: The use of DigniCap minimize alopecia in a 84%, including pts with more than one chemotherapy regimen, in a a safety level.

Citation Format: Hernandez RE, Gerson R, Olivares G, Rivera S, Serrano A, Villalobos A, Lazaro M. Experience in the ABC Medical Center of Mexico City 2010-2015 using scalp-cooling system (DigniCap) for prevention of alopecia induced by chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-13.
Abstract P5-13-03: Prospective study of work limitations in breast cancer patients (pts) undergoing curative chemotherapy (CTx)
Authors: Tevaarwerk AJ , Buhr KA , Conkright W , Onitilo A , Robinson E , Hegeman R , Ahuja H , Kwong RW , Nanad R , Dennee A , Koehn T , Burkard ME , Wisinski KB , Wiegmann DA , Sesto ME
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P5-14-07: Impact of time to treatment (TTT) on recurrence free survival in non metastatic invasive breast cancer
Authors: Tiwari SR , Elson P , Tullio K , Budd GT
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-01-06: Glutamine metabolism drives breast cancer invasion by providing a source of extracellular glutamate to activate the GRM3 metabotropic glutamate receptor
Authors: Macpherson IR , Dornier E , Rabas N , Rainero E , Norman JC
Published: March 2017

Glutamine metabolism is well-established to contribute to cancer cell growth and proliferation by providing a source of nitrogen for nucleotide and amino acid biosynthesis as well as TCA cycle intermediates. There is also accumulating evidence that glutamine metabolism may contribute to metastasis although mechanistic links to tumour cell migration and invasion remain unclear. We have generated a number of highly invasive primary cell lines from the polyoma middle-T genetically engineered mouse model of breast cancer (MMTV-PyMT) and found that withdrawal of glutamine from these cells reduces not only their proliferation, but also their invasive migration into 'stroma-like' preparations of fibroblast-derived extracellular matrix. Our metabolomic analyses indicate that invasive MMTV-PyMT cells actively secrete glutamate, a product of glutamine metabolism, into the extracellular milieu. Moreover, addition of glutamate is sufficient to restore invasiveness (but not cell growth or proliferation) to glutamine-starved MMTV-PyMT cells. We have pursued these findings by investigating the role played by plasma membrane receptors for glutamate in cell migration and invasion in PyMT cells and in MDA-MB-231 triple negative breast cancer cells. We provide evidence that glutamate generated within the cell by deamidation of glutamine leaves the cell via the xCT antiporter to activate the GRM3 metabotropic glutamate receptor at the cell surface. This, in turn, suppresses adenylate cyclase activity to prevent protein kinase A activation and to drive an invasive programme. Indeed, knocking out GRM3 with CRISPR technology or inhibition using a selective GRM3 antagonist (LY341495) is sufficient to oppose invasiveness without compromising proliferation. Conversely, a specific GRM3 agonist (LY354740) drives invasiveness without increasing proliferation. Consistently, treatment with LY341495 was sufficient to abrogate lung colonisation following tail vein injection whilst tumour growth after orthotopic injection was unaffected. Our results provide a mechanistic link between glutamine metabolism and invasion and identify GRM3 as a potential therapeutic target in breast cancer.

Citation Format: Macpherson IR, Dornier E, Rabas N, Rainero E, Norman JC. Glutamine metabolism drives breast cancer invasion by providing a source of extracellular glutamate to activate the GRM3 metabotropic glutamate receptor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-01-06.
Abstract P6-01-07: Mitochondria-nuclear communication regulates epithelial-mesenchymal transition and metastasis in triple negative breast cancer
Authors: Park JH , Jung KH , Sirupangi T , Vithayathil S , Jin F , Putluri V , Piyarathna DWB , Yotnda P , Bhat VB , Sreekumar A , Lewis MT , Coarfa C , Putluri N , Creighton CJ , Wong L-JC , Kaipparettu BA
Published: March 2017

For triple negative breast cancer (TNBC), the driver pathways are still poorly understood. Advances in cancer metabolism research over the last decade have enhanced and modified our understanding on Warburg effect. It is now known that mitochondria in tumors are not always defective in their ability to carry out oxidative phosphorylation. Instead, in proliferating cells, mitochondrial energy pathways are reprogrammed to meet the challenges of macromolecular synthesis and to escape from apoptosis. Tumor initiating cells (TICs) maintain cancer stem cell properties and are known to play significant role in TNBC metastasis. Mitochondrial retrograde regulation (MRR) is a bidirectional communication between mitochondria and nucleus. MRR is triggered by mitochondrial functional demands and it responds in a continuous manner to change metabolic needs of the cell. Using transmitochondrial cybrid (cybrid) technology, we generated different cybrid models under common nuclear backgrounds of benign breast epithelium or TNBC. Mitochondria from cells with different cancer potential such as benign breast epithelium, moderately metastatic and highly metastatic breast cancer cell lines were studied under the common nuclear background to understand MRR-regulated TIC properties and cancer pathways. Using genomic, metabolomic, and proteomic approaches, we confirmed the significance of mitochondrial character in the regulation of epithelial mesenchymal transition (EMT), TIC and metastatic properties. Altogether, our results suggest that MRR is critical in TNBC TIC character and stemness.

Citation Format: Park JH, Jung KH, Sirupangi T, Vithayathil S, Jin F, Putluri V, Piyarathna DWB, Yotnda P, Bhat VB, Sreekumar A, Lewis MT, Coarfa C, Putluri N, Creighton CJ, Wong L-JC, Kaipparettu BA. Mitochondria-nuclear communication regulates epithelial-mesenchymal transition and metastasis in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-01-07.
Abstract P6-02-02: Uridine diphosphate glucose dehydrogenase is required for hyaluronic acid production and breast cancer invasion
Authors: Arnold JM , Rasaily U , Ramirez-Peña E , Pathak R , San Martin R , Purwaha P , Rao A , Putluri N , Rowley D , Sikora A , Mani S , Sreekumar A
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-04-01: Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy
Authors: O'Brien KP , Khan S , Thompson K , Joyce D , Lalor P , Dockery P , Ingoldsby H , Kerin MJ , Dwyer RM
Published: March 2017

Introduction: Mesenchymal Stem Cells(MSCs) are multipotent stromal cells that are known to engraft into tumours, raising their potential as tumour-targeted delivery vehicles. MSCs secrete tiny vesicles known as exosomes, which contain genetic material including microRNAs, and are effectively taken up by recipient cells. This study aimed to characterise a tumour-suppressing microRNA, miR-379, and engineer MSCs to secrete exosomes enriched with the microRNA.

Methods: The mechanism of action of miR-379 In Vivo was determined through lentivirus-mediated upregulation of miR-379 in breast tumours, and analysis of changes in tumour angiogenesis, proliferation and progression. Subsequently, MSCs were engineered with lenti-379 and any impact on MSC migration, proliferation and morphology was assessed. MSC-secreted exosomes were isolated and characterised using Transmission Electron Microscopy(TEM) and Western Blot. The exosomal microRNA content was analysed by RQ-PCR, and transfer between cell populations visualised using confocal microscopy.

Results: While elevated miR-379 expression did not impact tumour size In Vivo, an increase in tumour necrosis and decrease in invasion was observed. MSCs were successfully transduced with miR-379, resulting in a distinct change in cell morphology. Despite this, MSC-379 cells maintained inherent tumour-targeted migratory capacity, with no impact on proliferation observed. MSC-379 derived exosomes were 30-120nm in size and expressed the exosome-associated protein CD63. A 5-fold increase in miR-379 was observed in engineered exosomes. Successful transfer of RFP-labelled MSC-derived exosomes to breast cancer cells was visualised using confocal microscopy.

Conclusion: Engineering tumour-targeted MSCs to secrete exosomes enriched with miR-379 holds exciting potential as a novel therapy for breast cancer.

Citation Format: O'Brien KP, Khan S, Thompson K, Joyce D, Lalor P, Dockery P, Ingoldsby H, Kerin MJ, Dwyer RM. Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-04-01.
Abstract P6-05-01: Low BRCA2 levels cause epigenetic activation of growth adaptive pathways without inducing recurrent genomic mutations
Authors: Gruber JJ , Snyder M
Published: March 2017

The development of therapeutics to prevent cancer onset is hindered by a lack of robust cell systems to study the earliest steps of malignant transformation. Significant barriers to studying cancer-initiating events include intrinsic cellular pathways to prevent cell proliferation in the setting of activating oncogenes or genomic instability. To circumvent this limitation, we studied in vitro transient depletion of breast cancer tumor suppressor genes followed by selective growth conditions to enrich for de novo mutations or stable epigenetic alterations that can confer a growth advantage to non-transformed breast epithelial cells. We report that transient BRCA2 depletion, but not depletion of other breast cancer genes, leads to a selective growth advantage in EGF-free media. This is due to a failure of BRCA2 inactivated cells to enact a mesenchymal-to-epithelial transition upon withdrawal of EGF. Genomic profiling and biochemical approaches indicate that transient loss of BRCA2 induces chromatin remodeling in concert with NF-κB signaling and histone H2B deacetylation to repress genes associated with the epithelial state. Notably, this process did not appear to require recurrent driver mutations, nor DNA methylation changes, but was dependent on ATR signaling. Overall, our work suggests that transiently low BRCA2 levels are sufficient to induce aberrant cell proliferation under certain conditions and that targeting epigenetic modifiers may be an approach to prevent BRCA2-induced malignancy.

Citation Format: Gruber JJ, Snyder M. Low BRCA2 levels cause epigenetic activation of growth adaptive pathways without inducing recurrent genomic mutations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-05-01.
Abstract P6-07-18: A pilot study of the impact of a single dose of zolendronic acid on biomarkers in breast cancer
Authors: Cho M , Gong J , Chen S , Yu H , Wong L , Kruper L , Mortimer J
Published: March 2017

Backgrounds: In randomized trials for early stage breast cancer, patients who received adjuvant zolendronic acid (ZA) had superior disease-free survival and greater tumor shrinkage. Preclinical data suggest that ZA has anti-cancer properties by modulating angiogenesis and tumor immune environment. This is the pilot study to assess changes in tumor biomarkers and immunological function in response to a single dose of ZA in paired tumor specimens (from core biopsy and definitive surgery).

Methods: Postmenopausal women with early stage invasive ductal breast carcinoma who have estrogen receptor and/or progesterone receptor positive tumor for which a lumpectomy or mastectomy was planned prior to systemic therapy were enrolled. A single dose of ZA 4mg IV was given 10-14 days prior to their planned definitive surgery. 14 biomarkers in tumor tissue was assayed; 10 by gene microarray (VEGF, IL1β, IL-6, MMP-1, MMP-2, MMP-9, TGF, Interferon α and STAT3)) and 4 by RT-PCR(P13K, PTEN, IGF-1-R, EGFR. Patient blood samples were drawn at baseline, at 48-72hrs after the single dose of ZA and at the time of surgery and assayed for cytokines and chemokines by using 30-plex Luminex panels.

Results: Eight patients were enrolled in the study (median age 65 and range (57-75); 4 caucatians, 2 hispanic and 1 asian; 6 stage I, 1 stage II and 1 stage III). 30-plex luminex assays showed MIG, IP-10 and IL-12 were found to increase in Day 1-3 of ZA therapy from baseline and normalized by Day 10-24. MCP-1, IL2R, MIP-1b and Eotaxin were found to have changes in Day 1-3 from baseline and mix outcome by Day 10-24. EGF, G-CSF, HGF, IFN-alpha and IFN-gamma and RANTES showed no clear pattern among eight patients. Tumor markers and proteomics from pair tumor samples will be presented.

Conclusions: Changes in multiple tumor biomarkers and immunological markers, MIG, IP-10, IL-12, MCP-1, IL2R, MIP-1b, Eotaxin, IFN-alpha and IFN-gamma are seen within 2 weeks of a single dose of ZA.

Citation Format: Cho M, Gong J, Chen S, Yu H, Wong L, Kruper L, Mortimer J. A pilot study of the impact of a single dose of zolendronic acid on biomarkers in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-18.
Abstract P6-07-31: Molecular mechanism of alcohol-associated breast cancer
Authors: Zhong S , Zhang Y , Lei J , Li W , Wu Z , Shi G
Published: March 2017

Epidemiological studies have indicated that alcohol consumption is an established risk factor for breast cancer. The association of alcohol consumption and breast cancer is more pronounced in ER+ cases than in ER- cases. However, this molecular mechanism remains to be determined. Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, increasing translational capacity to promote cell transformation and tumor formation. Our results reveal that alcohol increases Pol III gene transcription in both normal and cancer breast cell lines. The induction of Pol III genes by alcohol in ER+ breast cancer cells is significantly higher than in ER- normal breast cells and ER- breast cancer cells. E2 causes slight increase in Pol III gene transcription. The addition of ethanol to this system produces a marked increase. Alcohol increases ERa expression to enhance the cellular levels of Brf1 protein and mRNA. In addition, ethanol markedly stimulates phosphorylation of JNK1. Inhibition of JNK1 decreases ERE-Luc reporter activity and represses expression of ERa, Brf1 and Pol III genes. Reduction of ERa by its siRNA represses Brf1 and Pol III gene transcription. Ethanol with E2 produces larger and more numerous colonies. Repression of ERa or Brf1 inhibits alcohol-induced cell transformation. More interestingly, human biopsies studies show that Brf1 expression is significantly increased in nuclei of breast cancer cells, compared to tissue adjacent to the carcinoma. Together, these results support the idea that alcohol increases ERa expression through JNK1 pathway to elevate Brf1 expression and Pol III gene transcription, leading to greater phenotypic changes. ERa mediates Pol III gene transcription through Brf1, suggesting that ERa play a critical role in alcohol-induced deregulation of Pol III genes in ER+ breast cancer development.

*: The project is supported by NIAAA/NIH grants: AA017288, AA021114 and AA02324 to S Zhong.

Citation Format: Zhong S, Zhang Y, Lei J, Li W, Wu Z, Shi G. Molecular mechanism of alcohol-associated breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-31.
Abstract P6-09-06: Updating the AJCC TNM staging system a summary of changes
Authors: Hortobagyi GN , Giuliano A , Winchester DJ , Mittendorf E , Edge S , Connolly J , Weaver D , Rugo H , Solin L
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-09-34: Clinical and pathological characteristics of a representative cohort of long-term metastatic breast cancer (MBC) survivors
Authors: Giesler DL , Rosenzweig MQ , Diergaarde B , Puhalla SL
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-09-42: The role of serum neutrophil-to-lymphocyte ratio (NLR) in triple-negative breast cancer
Authors: Lee J , Song BJ , Chae BJ , Lee A , Kim SH , Kang BJ
Published: March 2017

This abstract was not presented at the symposium.
Abstract P6-09-55: “Quality, not quantity”: 10X hot-spot (HS) analysis of lymphocyte markers (CD3, CD8, CD4, CD20) in tumor-infiltrating lymphocytes (TILs) is superior to whole tumor (WT) analysis in triple-negative breast cancer (TNBC)
Authors: Cui X , McIntire PJ , Ginter PS , Irshaid L , Chen Z , Shin SJ
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-09-57: Stromal density of tumor-infiltrating lymphocytes (TILs): Challenging the 50% threshold that defines lymphocyte predominant breast cancer (LPBC)
Authors: McIntire PJ , Cui X , Ginter PS , Irshaid L , Chen Z , Shin SJ
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P6-16-03: Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC)
Authors: Paplomata E , Gogineni K , Meisel J , Santa-Maria C , Yuan L , Kramer J , Bill Li X , Zelnak A , Pakkala S , Kaklamani V , O'Regan R
Published: March 2017

Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer.

Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death.

Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction.

Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340.

Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-03.
Abstract PL2: Cell free plasma tumor DNA in breast oncology
Authors: Park BH
Published: March 2017

In the past decade, there has been great interest in the use of circulating cell-free DNA to help guide therapy decisions in clinical oncology. Recent work by our group and others suggests that circulating cell-free plasma tumor DNA offers advantages compared to tissue biopsies for mutation profiling. This concept of “liquid biopsy” may allow for a more global genomic picture of metastatic disease since blood serves as a reservoir for all metastatic sites. In addition, cell-free plasma tumor DNA can be measured serially and quantitatively, presenting the possibility of using circulating plasma tumor DNA as a biomarker to measure disease burden and response to therapies for both early and late stage disease. In this session, I will review historic and recent studies demonstrating the clinical potential of measuring cell-free plasma tumor DNA in breast cancer patients for early stage and metastatic disease. I will also outline future steps needed to translate liquid biopsies from research use to clinical practice, and recent work highlighting the first multi-institutional prospective clinical trial evaluating cell-free plasma tumor DNA in early stage breast cancer patients undergoing neoadjuvant chemotherapy.

Citation Format: Park BH. Cell free plasma tumor DNA in breast oncology [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PL2.
Abstract S1-04: Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05)
Authors: Blok EJ , van de Velde CJH , Meershoek-Klein Kranenbarg EM , Putter H , van den Bosch J , Maartense E , van Leeuwen-Stok AE , Liefers G-J , Nortier JWR , Rutgers EJT , Kroep JR
Published: March 2017

Despite the success of adjuvant endocrine therapy in early breast cancer, approximately 50% of all recurrences still occur after the initial 5 years of follow-up. Earlier studies confirmed that endocrine therapy extension after 5 years of adjuvant tamoxifen with either tamoxifen or aromatase inhibitors up to 10 years leads to an improvement in survival. However, aromatase inhibitors are currently standard of care in the initial 5 years of adjuvant therapy, and the benefit of extended use beyond 5 years of AI based therapy is still debated. The randomized phase III IDEAL trial was designed to study the optimal duration of extended adjuvant endocrine therapy after the initial 5 years of any endocrine therapy.

Between April 2007 and November 2011, 1824 postmenopausal, HR-positive early breast cancer patients were included by 74 hospitals in the Netherlands. Enrolled patients earlier received 5 years of any endocrine therapy (87.9% AI based),completed this treatment no longer than 2 years before randomization, and did not have any recurrence at the moment of inclusion. The included patients were randomly allocated to either 2.5 or 5 years of extended letrozole (daily 2.5mg). Primary outcome was disease free survival (DFS), secondary endpoints were overall survival (OS), distant disease free survival (DDFS), contralateral breast cancer and safety.

Results & Discussion: Results will become available soon.

Citation Format: Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, Kroep JR. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-04.
Abstract S2-01: Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients
Authors: Couch FJ , Hu C , Lilyquist J , Shimelis H , Akinhanmi M , Na J , Polley EC , Hart SN , McFarland R , LaDuca H , Huether R , Goldgar DE , Dolinsky JS
Published: March 2017

Clinical genetic testing panels are broadly used to gather information about cancer predisposition in individuals with personal and/or family history of breast cancer. However, the involvement of several of the genes on clinical testing panels in predisposition to breast cancer, such as MRE11A and RAD50, has recently come into question. In addition, accurate risk estimates for breast and other cancer are not well defined for the majority of genes on testing panels. We studied 60,000 women diagnosed with breast cancer who were tested for germline cancer predisposing mutations using hereditary cancer gene panels. Information on personal and family cancer history, age of diagnosis, and ethnicity of patients was obtained from test requisition forms. Greater than 90% met National Comprehensive Cancer Network HBOC testing criteria. To estimate gene-specific risks for breast cancer, case-control analyses were performed comparing the frequencies of pathogenic mutations from Caucasian cancer cases with frequencies from Caucasian, non-Finnish, non-TCGA controls from the Exome Aggregation Consortium (ExAC) database. Mutations were detected in 9% of breast cancer patients. Twelve genes displayed a significant association (p<0.05) with breast cancer. Nine of these genes, including ATM, RAD51D, NF1, and MSH6, were associated with moderate risk (RR>2.0) of breast cancer and three genes (BRCA1, BRCA2, PALB2) were associated with high risk (RR>5.0) of breast cancer. Cumulative age-dependent risk models were developed for each gene. This large clinical testing dataset of 60,000 women with breast cancer provides useful data for many predisposition genes previously lacking risk estimates, and should prove useful for clinical risk management of patients with inherited mutations in these genes.

Citation Format: Couch FJ, Hu C, Lilyquist J, Shimelis H, Akinhanmi M, Na J, Polley EC, Hart SN, McFarland R, LaDuca H, Huether R, Goldgar DE, Dolinsky JS. Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-01.