bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3696A: The detection and prediction of circulating tumor cells in breast cancer patients
Authors: Molloy Tim , Helgason Helgi H , Bosma Astrid , van't Veer Laura J.
Published: May 2019

The detection of circulating tumor cells (CTC) in the blood of cancer patients is a promising tool for risk stratification, treatment tailoring, and monitoring of the disease state. The current study aims to develop a QPCR-based detection platform for the semi-quantitation of tumor cell load in the peripheral blood of breast cancer patients by combining gene expression data from 4 tumor marker genes into a single index-score. From a cohort of 131 individuals, CTC index-score positivity, indicating tumor cell presence, was observed in 14 out of 16 (88%) metastatic patients, 16 out of 87 (18%) non-metastatic stage I-III patients, and 0 out of 28 (0%) healthy female controls. A previous study demonstrated that CTC index-score positivity in metastatic patients correlated to a significantly shorter time to disease progression. This CTC detection platform demonstrates high specificity (100%) and sensitivity (88%), and can be an effective clinical tool providing valuable prognostic information.

This CTC detection assay was subsequently compared to a CTC prediction assay developed using microarray expression data from the primary tumors of the patients from the same cohort. From 73 patients, a CTC predictive tumor profile was developed with the ability to distinguish those patients with a positive CTC QPCR index-score from those with a negative index-score with an average 83% internal cross-validation accuracy. When a small independent test set was assayed, those patients classified on the basis of their tumor gene expression as having a positive CTC QPCR score had a shorter interval to metastasis development (mean = 29.6 months) versus those predicted to have a negative score (mean = 51.4 months).

When the QPCR-based and microarray-based CTC assays were compared directly, and each in combination with the “70-gene prognosis signature” for distant metastasis prediction, the CTC predictive microarray assay was superior to the CTC QPCR assay both alone and in combination with the 70-gene profile for time interval to metastasis. This study demonstrates that a microarray model predictive of tumor cell dissemination has prognostic value and seems independent of other metastasis-predictive microarray profiles.
Abstract 3839: Is recent decline in breast cancer incidence equal across different US racial groups?
Authors: Huo Dezheng , Olopade Olufunmilayo I
Published: May 2019

Background: Recently, a sharp decline in breast cancer incidence rate was observed between 2002 and 2003 in the United States, evident only in women aged 50 years or older and for estrogen-receptor positive breast cancer. The plausible explanations for the decline have been controversial. Moreover, it is unclear if the reduction in incidence is equally distributed across all racial groups or whether the trends in breast cancers of different stages are similar.

Methods: We examined temporal trends between 2000 and 2004 in invasive and in situ female breast cancer by race and tumor stage, using data from 17 cancer registries of the Surveillance, Epidemiology, and End Results program. Incidence rates were age-adjusted to the 2000 US standard population. We used jointpoint regressions to fit a series of joined straight lines on a log scale to the trends of quarterly, age-adjusted rates in women aged 50 to 69 years.

Results: In Caucasian women, the incidence rate of invasive breast cancer was stable from 2000 to mid-2002 (-0.15% per quarter), significantly decreased to the end of 2003 (-2.41% per quarter, p=0.004), and stable to the end of 2004 (0.63% per quarter). Similar trends were seen for the rates of localized tumors and regional and distant tumors in Caucasians. The incidence rate of invasive breast cancer did not change significantly in the other racial groups: the quarterly changes throughout the study period were 0.07% in African Americans, -0.14% in American Indian/Alaska Natives, and -0.46% in Asian American/Pacific Islanders. The incidence rate of in situ breast cancer was stable in Caucasians (-0.23% per quarter), African Americans (0.26% per quarter), and American Indian/Alaska Natives (-0.97% per quarter). In Asian American/Pacific Islanders, the rate of in situ breast cancer was marginally significantly increased from 2000 to the mid-2002 (2.09% per quarter, p=0.054) but decreased to the end of 2004 (-3.20% per quarter, p=0.01).

Conclusions: The decline in breast cancer incidence was not equal across US racial groups and the benefit was confined to Caucasians. This racial disparity is consistent with the hypothesis that discontinuation of hormone replacement therapy (HRT) may have caused the dramatic reduction. Compared with Caucasians, African Americans are more likely to have estrogen receptor negative tumors and less likely to use HRT, and thereby less likely to show a benefit from discontinuation of HRT. The finding that the rate of invasive breast cancer (but not in situ cancer) decreased suggests that exogenous estrogen serves as a promoter rather than an initiator of breast cancer. The trend of in situ cancer in Asian American/Pacific Islanders may be a result of slower uptake of mammographic screening in this population.
Abstract 4908: Antennapedia "trojan" peptide delivers p21 protein resulting in tumor eradication
Authors: Kousparou Christina , Deonarain Mahendra , Stylianou Spyros , Epenetos Agamemnon
Published: May 2019

The purpose of this study is to utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo.

Many cell-translocating trojan peptides have been studied in the context of therapeutic protein delivery, including the homeodomain region of the Drosophila Antennapedia protein. The mechanism of transduction of this peptide relies on the presence of basic aminoacids arranged in helical conformations, which are important for lipid interactions and for penetration of the membrane.

The tumor-suppressor protein p21 is important in many key cell division processes including G1 arrest leading to apoptosis of damaged cells. Restoring p21 protein to tumor cells lacking functional p21 could lead to tumor cells regaining higher chemosensitivity and the ability to die upon genotoxic insult.

Our experiments investigate the tumor inhibitory and therapeutic potential of a fusion protein comprising of the ‘trojan’ peptide Antennapedia and p21. The effects of administration of Antennapedia-p21 on the growth of cultured cancer cells and on tumors implanted into nude mice were evaluated. In vitro studies showed that nuclear localization of p21 protein could be achieved using the Antennapedia carrier. The efficacy of this treatment on cells was also determined in combination with conventional chemotherapy. Treatment with Antp-p21 induced cell-cycle arrest leading to the inhibition of tumor cell growth.

Intra-venous administration of the fusion protein to tumor-bearing mice inhibited tumor growth and prolonged overall survival. Furthermore, co-administration of the fusion protein with conventional chemotherapeutic agents resulted in enhanced growth inhibitory effects, tumor eradication in 40% of animals and significant reduction in tumor burden in 100% of animals.

In conclusion, our findings show that we can utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo and achieve tumor eradication. The efficacy of our anti-tumor growth modality in combination with conventionally used anti-neoplastic medication suggests that it can be considered as a promising therapeutic drug for the management of a wide range of carcinomas.
Abstract 5000: The functional stem cell marker aldehyde dehydrogenase enhances pancreatic cancer stem cell isolation and correlates with clinical prognosis
Authors: Rasheed Zeshaan A , Yang Jie , Wang Qiuju , Freed Irwin , Koorstra Jan-Bart , Hong Seung-Mo , He Xiaobing , Berman David , Laheru Daniel , Hidalgo Manuel , Jimeno Antonio , Maitra Anirban , Matsui William H
Published: May 2019

Pancreatic adenocarcinoma is a highly aggressive cancer that is largely resistant to current therapies and portends a median survival for patients of 9-12 months. Resistance may be due to a subpopulation of cells that are chemoresistant and able to support tumor propagation, such as cancer stem cells (CSCs). CSCs have emerged as attractive therapeutic targets, but the development of effective therapies requires the isolation of highly purified cell populations. Surface antigen expression has been used to identify CSC in most systems, however, methods based on functional properties, such as Hoechst dye exclusion or aldehyde dehydrogenase (ALDH) activity, can enhance stem cell isolation from normal and malignant tissues. We compared CSCs from pancreatic adenocarcinomas isolated by cell surface phenotype, ALDH activity, or both. Initially, we studied ALDH expression in human pancreatic cancer cell lines (CAPAN-1, DAN-G, CFPAC-1) using the Aldefluor assay. We found that each line contained a small population of ALDH+ cells (0.9-6.5% of total cells) that demonstrated increased clonogenic growth potential both in vitro and in vivo compared to ALDH- cells. Next, we compared ALDH expression with the published pancreatic CSC phenotype (CD24+CD44+) in cell lines and low-passage xenografts derived from primary human tumor specimens. Interestingly, we found that the putative CSC populations were only partially overlapping since 7-18.2% of the ALDH+ cells were CD44+CD24+ and only 4.2-36.2% of the CD44+CD24+ cells expressed ALDH. We compared CD44+CD24+ and CD44+CD24+ALDH+ cells isolated from 5 unique human pancreatic cancer xenografts and found that the CD44+CD24+ALDH+ cells were more tumorgenic in NOD/SCID mice. We also evaluated ALDH expression in primary pathologic specimen from 268 patients with pancreatic cancer by immunohistochemistry and found small, intensely positive cells with round or oval nuclei near the base of cancerous glands or at the invasive front in 90 (34%) of those patients. Furthermore, the presence of these cells was significantly associated with poorer overall survival (14 vs. 18 mos, p=0.02). We have begun to evaluate the mechanism by which pancreatic CSCs may be involved in more aggressive disease and found that CD44+CD24+ALDH+ cells isolated from tumor xenografts have significantly lower expression of E-cadherin and higher expression of Slug, a transcriptional repressor of E-cadherin, compared to ALDH+ or ALDH- cells. Therefore, ALDH appears to mark highly clonogenic pancreatic CSCs. Moreover, increased features associated with epithelial-to-mesenchymal transition may play a role in the correlation of ALDH+ cells with long-term outcomes.
Abstract 557: Aging and DNA methylation in Alu and LINE-1 repeated elements
Authors: Cantone Laura , Bollati Valentina , Wright Robert , Litonjua Augusto , Tarantini Letizia , Suh Helen , Sparrow David , Vokonas Pantel , Baccarelli Andrea , Schwartz Joel
Published: May 2019

DNA methylation exhibits a gradual genome-wide decrease in association with aging and the rate of decrease appears to be inversely proportional to life expectancy. The observed age-related increase in cancer incidence cannot be explained entirely by genetic mutation rates. Accumulation of epigenetic alterations during aging may contribute to determine the malignant transformation. In particular, global DNA hypomethylation, which has been associated with repetitive DNA demethylation may promote chromosomal instability. About 55% of the human genome consists of repetitive elements, which are for the most part made up of approximately 500,000 long interspersed nucleotide elements (LINE elements) and 1.4 million Alu repetitive elements, which are normally heavily methylated. DNA methylation of LINE-1 and Alu elements has shown to correlate with total 5mC content and thus used to estimate global DNA methylation. In humans, LINEs are the major source of insertional mutagenesis, being involved in both germinal and somatic mutant phenotypes. Alu retrotransposition has also been associated with human disease. However, whether LINE/Alu methylation decreases with age has never been established.

We examined the epigenetic effect of aging on DNA methylation in repetitive elements Alu and LINE-1, measured in peripheral blood DNA from 693 subjects evaluated between 1999-2006 as part of the Normative Aging Study (NAS), a longitudinal study established in 1963 by the U.S. Veterans Administration. We measured DNA methylation through quantitative analysis by PCR-Pyrosequencing. Two different blood samples, taken approximately three years apart, were available for each subject.

Repeated element methylation was negatively associated with age. In linear regression, we found a decrease equal to 0.016% for LINE-1 (p=0.07) and 0.015% for Alu (p=0.007), for each year increase. We did not find significant changes between repeated measures taken three years apart from each other on the same subjects. The two repeated measures showed high correlation for both Alu (n=300, r=0.46, p<0.001) for Alu and LINE-1 (n=303, r=0.59, p<0.001).

DNA methylation of LINE-1 and Alu repetitive elements is inversely correlated with age, although is not captured in repeated measurements taken over a three years period. Such age-related decrease in methylation may increase the risk of mutational events potentially leading to cancer development.
Abstract 5814: Association between ADH1B and ADH1C haplotype tag SNPs and breast cancer risk, and the interaction with alcohol drinking
Authors: Marian Catalin , Sucheston Lara , Nie Jing , Millen Amy , Goerlitz David , Trevisan Maurizio , Russell M , Nochajski T , Ambrosone CB , Hutson A , Edge SB , Vito D , Shields Peter G , Freudenheim Jo L
Published: May 2019

Alcohol consumption has been found to be associated with breast cancer with some consistency. Alcohol dehydrogenase is rate limiting in alcohol metabolism. We investigated the association of haplotype tag SNPs in ADH1B and ADH1C with breast cancer risk and the interaction with alcohol drinking in a population-based case control study (the WEB Study) conducted in western New York between 1996 and 2001. Genomic DNA and SNP genotyping was performed by allelic discrimination real time PCR for 991 cases and 1698 controls. Haplotype tag SNPs were selected from the Caucasian HapMap data. Lifetime alcohol consumption was queried by interview. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Backwards selection was employed to obtain the most parsimonious model starting with the full model with interactions. Two tag SNPs, rs1042026 in ADH1B and rs1614972 in ADH1C, were associated with risk for postmenopausal women. The ADH1B SNP rs1042026 located in the 3’UTR is in LD with several functional SNPs from ADH6, ADH1A, ADH1B and ADH1C. This SNP was in Hardy Weinberg equilibrium in the postmenopausal control and not in postmenopausal cases, which strengthens the evidence of association. This SNP showed evidence of significant interaction with alcohol consumption. The OR for postmenopausal breast cancer in women with both CC genotype and who consume alcohol versus without the AA genotype and who abstain was 1.94, 95%CI 1.13-3.30. In addition, we found evidence of a trend for dose response depending on the amount of alcohol consumption when alcohol consumption was examined in three categories of abstainers, low and high consumption (p=0.08). The ADH1C SNP rs1614972 located in intron 8 is in LD with other six nonsynonymous exonic SNPs including the functional I350V (rs698). There was an interaction with alcohol consumption with the presence of the CC genotype and risk conferring a protective effect varying inversely proportional with the drinking level (p=0.0092). Moreover, the CC genotype decreased the odds of breast cancer in women who consume alcohol versus those that abstain regardless of the menopausal status (OR=0.56, 95%CI 0.35-0.90). In conclusion, haplotype tag SNPs in ADH1B and ADH1C were associated with breast cancer risk especially in postmenopausal women, and showed evidence of significant interaction with alcohol consumption.

Supported by the following grants: DAMD-17-03-1-0446, DAMD-17-00-1-0417 and NCI-RO1CA92040

Marian C. was supported by an AVON-AACR International Scholar in Breast Cancer Research award
Abstract LB-202: Phase 1 dose escalation trial of the novel vascular disrupting agent NPI-2358
Authors: Mita Monica , Spear Matthew A , Yee Lorrin K , Papadopoulos K P , Heath Elisabeth , Romero Ofelia , Lloyd G Kenneth , Cropp Gillian , Mita Alain , LoRusso Patricia
Published: May 2019

Background: NPI-2358 is a novel vascular disrupting agent that inhibits tubulin polymerization leading to tumor vascular endothelial destabilization. NPI-2358 selectively induces tumor vascular collapse resulting in tumor regression and potentiates other oncology agents in preclinical tumor models. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity.

Methods: In this study the dose of NPI-2358 was escalated from 2 to 30 mg/m2 in patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 was escalated in cohorts, in which any cohort could consist of 1 patient provided no ≥Grade 2 adverse event is reported in the prior cohort, otherwise the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO, and PK were obtained on day 1 and day 15. DCE-MRI were performed at baseline, day 2 then every other cycle and end of study as feasible, to assess changes in tumor blood flow and vascular permeability as reflected in the volume transfer constant (Ktrans). An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of Ktrans by eliminating variability associated with subject motion, contrast injection, and cardiac output.

Results: Twenty-five subjects were enrolled in the dose escalation phase. We selected 30 mg/m2 as the RP2D, based on adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16-82% decrease in patients evaluated at 30 mg/m2. Decreasing Ktrans over multiple treatment cycles was seen in the two patients that underwent repeat DCE-MRI imaging. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles), and melanoma (2 cycles). Average Cmax and AUCtotal have increased from 34 to 610 ng/ml, and from 101 to 3998 ng/ml/hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.8 ±3.2 h, CL was 34.1 ±26 L/h, and Vss was 211±61 L.Conclusions: At the RP2D NPI-2358 produced tolerable toxicities, while eliciting decreases in tumor blood flow by DCE-MRI. Maximum effect on Ktrans appeared to increase with increasing dose and time on treatment. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently proceeding into Phase Ib/II trials in solid tumor malignancies.
Abstract LB-239: An rnai sensitization screen identifies compensatory IKKα activation during IKKβ inhibition
Authors: Lam Lloyd T , Davis R. Eric , Ngo Vu , Wright George , Lenz Georg , Zhao Hong , Yu Xin , Dang Lenny , Staudt Louis M
Published: May 2019

Introduction: We previously described a subtype of diffuse large B-cell lymphoma (DLBCL) termed activated B-cell-like (ABC) DLBCL that depends on NF-κB activity for survival, and showed that a specific small molecule inhibitor of the upstream kinase IKKβ is selectively toxic to this subgroup of lymphoma.

Methods: To identify proteins or pathways whose inhibition may synergize with the toxicity of IKKβ inhibition in ABC DLBCL, we performed an “RNAi sensitization” screen with an RNA interference library, directed against 500 protein kinases, in the presence of the specific IKKβ inhibitor in an ABC DLBCL cell line.

Results: Short hairpin RNA (shRNAs) targeting IKKα, a component of the IKK complex, enhanced killing by the IKKβ inhibitor in ABC DLBCL cell lines but not other lymphoma cell lines. Gene expression profiling and NF-κB-specific reporter assays showed that IKKα shRNA affects the classical NF-κB pathway, further inhibiting the phosphorylation of IκBα only in the presence of the specific IKKβ inhibitor. Further studies in physiologic models of lymphocyte stimulation showed that compensatory IKKα activity occurs in other settings.

Conclusions: These results demonstrate that loss-of-function screens in the presence of a defined inhibitor can identify therapeutic targets in cancers, providing a rationale for combination therapies targeting multiple pathways critical to an individual cancer.
Abstract P1-03-06: Improvement in risk predictive value of Nottingham prognostic index by determining GP88 tumor tissue expression for estrogen receptor positive breast cancer patients
Authors: Serrero G , Hawkins DM , Bejarano PA , Ioffe O , Tkaczuk KR , Elliott RE , Head JF , Phillips J , Godwin AK , Weaver J , Hicks D , Yue B
Published: May 2019

Background: The Nottingham Prognostic Index (NPI), which includes nodal status, tumor size and histological grade was established to provide predictive value information on post-surgery survival for primary breast cancer patients. Attempts to improve NPI's performance have included addition of other biomarker expression and morphological features such as vascular invasion. In the present study, we investigated whether expression of the autocrine growth and survival factor GP88 (progranulin), known to be overexpressed in breast cancer, whereas it is negative in normal mammary tissue, would improve NPI's predictive value.

Methods: We examined the tumor tissue GP88 expression by immunohistochemistry (IHC) in formalin fixed paraffin embedded tissue sections from 508 cases of estrogen receptor positive (ER+) invasive ductal carcinoma (IDC) with known clinical outcomes (disease-free and overall survivals) and with known NPI. GP88 IHC tumor tissue expression was determined using an anti-GP88 antibody (clone 6B3) developed in our laboratory. GP88 expression was scored (0, 1+, 2+, 3+) by two board certified pathologists and classified into two IHC score groups of GP88 < 3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) and overall survival (OS) outcomes was then examined by Kaplan Meier analysis, Cox proportional Hazard (CPH) ratio and Pearson's C2 test.

Results: Kaplan-Meier survival graphs categorized by NPI scores (< 3.4, 3.4-5.4, and >5.4) and by GP88 expression (< 3+ and 3+) showed that for each NPI subgroup, patients with GP88 IHC score of 3+ had a worse disease-free survival (DFS) and overall survival (OS) than patients within the same NPI subgroup with tumors that had GP88 IHC score < 3+. When adjusted for NPI, high GP88 score was highly significantly associated with recurrence with a hazard ratio of 3.30 (95% CI 2.12 to 5.14).

Conclusions: The data suggest that measuring GP88 tumor tissue expression by IHC at time of diagnosis for breast cancer patients with primary ER+ IDC could provide recurrence prediction and survival information complementary to that provided by the determination of NPI alone and thus may be useful for risk management of patients diagnosed with breast cancer.

Citation Format: Serrero G, Hawkins DM, Bejarano PA, Ioffe O, Tkaczuk KR, Elliott RE, Head JF, Phillips J, Godwin AK, Weaver J, Hicks D, Yue B. Improvement in risk predictive value of Nottingham prognostic index by determining GP88 tumor tissue expression for estrogen receptor positive 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 P1-03-06.
Abstract P1-09-10: Pathological complete response to neoadjuvant trastuzumab is dependent on HER2/CEP17 ratio in HER2-amplified early breast cancer
Authors: Singer CF , Tan YY , Fitzal F , Steger GG , Egle D , Reiner A , Rudas M , Gruber C , Bartsch R , Fridrik M , Seifert M , Exner R , Balic M , Bago-Horvath Z , Filipits M , Gnant M ,   For the Austrian Breast and Colorectal Cancer Study Group
Published: May 2019

Purpose To evaluate whether pathological complete response to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.

Patients and Methods 114 women with HER2-overexpressing early breast cancer who had received neo-adjuvant trastuzumab in the prospective ABCSG-24 and ABCSG-32 trials, and for whom the HER2/CEP17 ratio was available, were included in this analysis. The ratio was correlated with tumor response as measured by the three most commonly used definitions of pathological complete response: ypT0 ypN0, ypT0/is ypN0, and ypT0/is.

Results In trastuzumab-treated patients, ypT0 pN0 was achieved in 69.0% of patients with a HER2/CEP17 ratio of >6, but only in 30.4% of tumors with a ratio of ≤6 (p=0.001, Chi Square test). When pCR was defined by ypT0/is pN0 or by ypTis, 75.9% and 82.8% of tumors with a high ratio had a complete remission, while only 39.1%, and 38.3% with a low ratio achieved a pCR (p=0.002 and p<0.001, respectively). Logistic regression revealed that tumors with a higher HER2/CEP17 ratio had a significantly higher probability to achieve ypT0 ypN0 (OR: 5.08, 95% CI 1.86-13.90; p=0.002) than tumors with a low ratio, while none of the other clinicopathological parameters was predictive of pCR. The association between high HER2 amplification and pCR was almost exclusively confined to HR positive tumors (62.5% vs. 24.0%, 75.0% vs. 28.0%, and 87.5% vs. 28.0%, for ypT0 ypN0, ypT0/is ypN0, and ypT0/is; p=0.014, p=0.005, and p<0.001), and was largely absent in HR negative tumors.

Conclusion A HER2/CEP17 ratio of >6 in the pre-therapeutic tumor biopsy is associated with a significantly higher pCR rate particularly in HER2 / HR co-positive tumors, and can be used to predict outcome before neoadjuvant trastuzumab is initiated.

Citation Format: Singer CF, Tan YY, Fitzal F, Steger GG, Egle D, Reiner A, Rudas M, Gruber C, Bartsch R, Fridrik M, Seifert M, Exner R, Balic M, Bago-Horvath Z, Filipits M, Gnant M, For the Austrian Breast and Colorectal Cancer Study Group. Pathological complete response to neoadjuvant trastuzumab is dependent on HER2/CEP17 ratio in HER2-amplified early 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 P1-09-10.
Abstract P2-05-24: Prognostic value of circulating PIK3CA mutations revealed with digital PCR in patients with HER2-positive advanced breast cancer: Results of West Japan Oncology Group study 6110BTR
Authors: Tsurutani J , Sakai K , Takao T , Kimura H , Kawabata H , Tanaka K , Takahashi M , Ito Y , Takao S , Aogi K , Sato K , Tsuji Y , Yamanaka T , Nakanishi Y , Saeki T , Nishio K
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P2-05-32: Tissue kallikrein-related peptidase 4, a novel biomarker in triple-negative breast cancer
Authors: Dorn J , Yang F , Aubele M , Kiechle M , Schmitt M
Published: May 2019

Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors estrogen receptor and progesterone receptor and not overexpressing the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded triple-negative breast cancer (TNBC) tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor cells and that of accessory stroma cells. In this patient cohort, elevated stroma KLK4 expression, but not tumor cell expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.

Citation Format: Dorn J, Yang F, Aubele M, Kiechle M, Schmitt M. Tissue kallikrein-related peptidase 4, a novel biomarker 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 P2-05-32.
Abstract P2-05-35: Rs1008805 polymorphism in CYP19A1 gene is related to the prognosis of early breast cancer
Authors: Shao X , Zheng Y , Huang P , Shi L , Wang X
Published: May 2019

This abstract was not presented at the symposium.
Abstract P2-06-03: The 3′UTR signature defines a highly metastatic subgroup of triple-negative breast cancer
Authors: Wang L , Hu X , Wang P , Shao Z-M
Published: May 2019

Purpose. Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with an aggressive clinical course. TNBC relapse or metastasis is associated with an unfavorable prognosis so predictive models are needed to chart potential patient outcomes. Alternative polyadenylation (APA) has recently gained attention as a major player influencing the kinetics of gene regulation under diverse physiological and pathological status, resulting in the dynamic usage of 3′ untranslated region (3′UTR). We postulate that alternative 3′UTR patterns, if incorporated into a single model, could improve postoperative risk stratification and identify a highly metastatic subgroup of TNBC. In this study, we used alternative 3′UTR patterns to improve postoperative risk stratification.

Experimental Design. We collected 327 publicly available microarrays and randomly stratified samples in a training (n = 164) and validation set (n = 163). Then, 1,933 3′UTRs were generated based on expression ratios of alternative 3′UTR. After initial feature filtering, we built a 17-3′UTR-based classifier using an elastic net model and validated the prognostic accuracy in both training and validation sets.

Results. Time-dependent ROC comparisons and Kaplan–Meier analyses confirmed an outstanding discriminating power of our prognostic model for TNBC patients. In the training cohort, 5-year event-free survival (EFS) was 78.6% (95% CI 71.2–86.0) for the low-risk group, and16.3%(95% CI 2.3–30.4) for the high-risk group (log-rank p < 0.0001; hazard ratio [HR] 8.29, 95% CI 4.78–14.4), In the validation set, 5-year EFS was 75.6% (95% CI 68.0–83.2) for the low-risk group, and 33.2% (95% CI 17.1–49.3) for the high-risk group (log-rank p < 0.0001; HR 3.17, 95% CI 1.66–5.42). The 17-3′UTR-based classifier could be used to independently predict outcomes and this outperformed prognosis using classical clinicopathological risk factors.

Conclusions. Our 17-3′UTR-based classifier provides a superior prognostic performance for estimating disease recurrence and metastasis in TNBC patients and it may permit personalized management strategies.

Citation Format: Wang L, Hu X, Wang P, Shao Z-M. The 3′UTR signature defines a highly metastatic subgroup of 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 P2-06-03.
Abstract P3-04-17: Global transcriptional repression by the coactivator SRC-1 mediates disease progression in treatment-resistant breast cancer
Authors: Ward E , Varešlija D , Fagan A , Hill A , Young L
Published: May 2019

Despite the effectiveness of endocrine therapy in treating estrogen receptor (ER) positive breast cancer, nearly 40% of breast cancer patients may develop resistance which can lead to metastatic disease progression. Steroid receptor co-activator-1 (SRC-1), a key regulator of ER signalling, is overexpressed in 35% of breast cancer patients and is strongly associated with the development of endocrine resistant metastasis(1). Recent studies highlighted the ability of SRC-1 to also act as transcriptional repressor. SRC-1 can therefore bi-directionally regulate gene expression to promote the resistant phenotype (2).

This study employed a genome-wide multi-omics sequencing approach to determine the SRC-1 repression signature in endocrine resistance and elucidate the mechanism by which SRC-1 mediates this repression. RNA-sequencing identified 736 genes significantly downregulated by SRC-1, with common functional pathways such as differentiation, cell morphogenesis and extracellular matrix enriched in the gene set. Parallel global methylation sequencing analysis revealed distinct differentially methylated regions specific to SRC-1 repressed target genes. Mechanistic studies in endocrine resistant cells revealed a role for methylation proteins, DNMTs and MBD, in SRC-1 directed repression. Through combined analysis of our global sequencing data we identified a network hub of five differentiation genes directly repressed by SRC-1. High expression of this signature predicts enhanced recurrence free survival in tamoxifen treated patients (n=335, p=0.032). A reduction in expression of these genes was shown to have functional output on proliferation, migration and mammosphere formation. Finally, we use tumour explant models to show that targeting DNA methylation can be used to reverse the SRC-1 driven suppression of this differentiation hub.

Here we report a novel mechanism by which SRC-1 may be driving endocrine resistant tumorigenesis. Our genome-wide discovery approach revealed a global epigenetic re-programming pathway whereby concerted differential DNA methylation is potentiated by the activation of SRC-1 in the presence of tamoxifen in the endocrine resistant setting. This study suggests that therapeutic strategies of combined targeted epigenetic therapy with estrogen deprivation could be a successful strategy to prevent acquired resistance to endocrine therapy.

Citation Format: Ward E, Varešlija D, Fagan A, Hill A, Young L. Global transcriptional repression by the coactivator SRC-1 mediates disease progression in treatment-resistant 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 P3-04-17.
Abstract P4-15-01: Cost-effectiveness of pre-implantation genetic diagnosis for BRCA mutation carriers
Authors: Lipton JH , Wong WWL , Warner E , Greenblatt EM , Lee EK , Chan KKW
Published: May 2019

Introduction: Management of BRCA mutation carriers is very expensive due to preventive surgeries and/or screening tests, as well as greater likelihood of cancer treatment. The related cancer burden and costs continue from generation to generation. One relatively new option for male or female BRCA mutation carriers, who wish to have children, is pre-implantation genetic diagnosis (PGD) of in vitro fertilized embryos. PGD eliminates the mutation from the descendants of these carriers. The purpose of this study was to model the cost-effectiveness of PGD.

Methods: We developed a Markov Model using TreeAge Pro 2016 and compared incidence of cancers, cancers-related death, costs, quality adjusted life-years (QALY), and incremental cost-effectiveness ratio (ICER) in the 2nd generation associated with conventional management of BRCA mutation carriers vs. PGD using a U.S. third-party payer's perspective with a lifetime horizon at a discount rate of 3% per year. In the model, health states were implemented to reflect the natural history of breast and ovarian cancer for women, and prostate cancer (and breast cancer in BRCA2 mutation carriers) for men. Model data were obtained from published literature. Costs were determined from published data and insurance payment schedules.

Results: Our preliminary results show that for BRCA1 mutation carriers, the PGD with IVF strategy is associated with an increase of 0.29 QALYs and costs an additional $292.68 per person, translating to an ICER of $1,014.25/QALY when compared with “No PGD”, making it highly cost-effective. For BRCA2 mutation carriers, the PGD with IVF strategy is associated with an increase of 0.17 QALYs and costs an additional $4,916.88 per person, translating to an ICER of $28,436.10/QALY when compared with “No PGD”, making it cost-effective.

Table 1StrategyCost ($)Incr Cost ($)Eff (QALY)Incr Eff (QALY)Incr C/E ($/QALY) BRCA 1     No PGD323,347.22 28.41  PGD323,639.89292.6828.70.291,014.25BRCA 2     No PGD318,723.02 28.52  PGD323,639.894,916.8828.70.1728,436.10

Conclusion: PGD for both BRCA1 and BRCA2 mutation carriers reduces cancer burden, increases QALYs and, is very cost-effective in the 2nd generation cohort, making this an attractive option from the perspectives of patients and public payers. Our estimates are conservative because the cost-effectiveness of PGD will likely improve further if subsequent generations are included in the model, given the expected further reduction in cancer burden and associated cost-savings in subsequent generations.

Citation Format: Lipton JH, Wong WWL, Warner E, Greenblatt EM, Lee EK, Chan KKW. Cost-effectiveness of pre-implantation genetic diagnosis for BRCA mutation carriers [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 P4-15-01.
Abstract P5-03-09: A high specificity and sensitivity qPCR Assay for HER2, ER and PR gene expression in breast cancer patients
Authors: Rinker KD , Fuh KF , McIntyre JB , Shepherd RD , Wang H-y , Morris D , Lee H
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P5-09-07: Impact of germinalcenter-associated nuclear protein polymorphisms on breast cancer risk and prognosis in a Japanese population
Authors: Kotani H , Ito H , Kuwahara K , Kuzushima K , Iwata H , Tsunoda N , Nagino M , Tanaka H , Matsuo K
Published: May 2019

Background: Germinal center-associated nuclear protein (GANP) is a phosphoprotein which is involved in mRNA export and the regulation of DNA recombination. We have previously demonstrated that deficiency of GANP led to spontaneous development of mammary gland tumors in a mouse model. In addition, we found that decreased GANP expression in human breast cancer tissue was an independent prognostic factor. Here, we conducted a case-control study and a retrospective cohort study to investigate whether single nucleotide polymorphisms (SNPs) of GANP are associated with sporadic breast cancer risk and prognosis in a Japanese population.

Subjects and Methods: Six hundred-ninety-four breast cancer cases and 1,376 age- and menopausal status-matched controls were selected within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Cases and controls were genotyped using an Infinium iSelect custom array (iCOGS, Illumina Inc., San Diego, CA, USA). We assessed 13 SNPs at the GANP locus, 2 SNPs (rs2839178 and rs11702450) were selected for further analysis by considering linkage disequilibrium. Conditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals. In addition, the survival impact of the two SNPs was retrospectively analyzed using the 694 breast cancer cases. To evaluate the effect of SNPs on overall survival (OS) and disease-free survival (DFS), multivariate Cox proportional hazards modeling was applied.

Results: Compared to the AA genotype of rs2839178, the GG genotype showed statistically significant associations with breast cancer risk (OR: 0.48, 95%CI:0.30–0.76, P = 0.002). In prognostic analysis, compared to those with the genotype AA at rs2839178, patients with AG or GG showed longer DFS (HR: 0.71, 95%CI: 0.49–1.04 and 0.42, 0.13–1.42, respectively, P for trend = 0.04). The GG genotype of rs2839178 also showed a positive tendency for longer OS although it was not statistically significant (HR: 0.69, 95%CI: 0.44–1.08, P = 0.11). We did not find that rs11702450 was associated with either breast cancer risk or prognosis.

Conclusion: This is the first study to investigate the association between GANP SNPs and breast cancer risk and prognosis. The direction of association with DFS was consistent with that of susceptibility. These results demonstrate that GANP SNPs presumably prevent the occurrence and malignant advancement of sporadic breast cancers.

Citation Format: Kotani H, Ito H, Kuwahara K, Kuzushima K, Iwata H, Tsunoda N, Nagino M, Tanaka H, Matsuo K. Impact of germinalcenter-associated nuclear protein polymorphisms on breast cancer risk and prognosis in a Japanese population [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 P5-09-07.
Abstract P6-01-01: The SIRT2 deacetylase stabilizes Slug to control malignancy of basal-like breast cancer
Authors: Zhou W , Kuperwasser C
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-01-02: Integration of whole-genome sequencing and functional screening to identify breast cancer lung metastatic drivers
Authors: Yang H-Y , Jiang Y-Z , Chen L , Zuo W-J , Di G-H , Hu X , Chen H-Q , Shao Z-M
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-01-03: N-terminus Slit2 suppresses breast cancer metastasis by inhibiting tumor associated macrophages
Authors: Ahirwar DK , Shehab RS , Mishra S , Shilo K , Ganju RK
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-01-12: Inhibiting ADP-ribosylation factor 1 activation to suppress breast cancer metastasis
Authors: Teng Y , Chavanieu A , Xie X
Published: May 2019

This abstract was not presented at the symposium.
Abstract P4-01-02: Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence
Authors: Coombes RC , Armstrong A , Ahmed S , Page K , Hastings RK , Salari R , Sethi H , Boydell A-R , Shchegrova SV , Fernandez-Garcia D , Gleason KL , Goddard K , Guttery DS , Assaf ZJ , Balcioglu M , Moore DA , Primrose L , Navarro SL , Aleshin A , Rehman F , Toghill BJ , Louie MC , Zimmermann BG , Lin C-HJ , Shaw JA
Published: May 2019

Background:

Many breast cancer patients relapse after primary treatment but there are no reliable tests to detect distant metastases before they become overt. Here we show earlier identification of recurring patients through a scalable personalised ctDNA analysis. The method is applicable to all patients, and not limited to hot-spot mutations typically detected by gene panels.

Methods:

Forty-nine non-metastatic breast cancer patients were recruited following surgery and adjuvant therapy. Plasma samples (n=208) were serially collected semi-annually. Using the analytically validated SignateraTM workflow, we determined mutational signatures from primary tumour whole exome data and designed personalised assays targeting 16 variants with high sensitivity by ultra-deep sequencing (average >100,000X). The patient-specific assay was used to detect the presence of the mutational signature in the plasma.

Results:

In 16 of 18 (89%) clinically-relapsing patients, ctDNA was detected ahead of metastatic relapse being diagnosed by clinical examination, radiological and biochemical (CA15-3) measurements, and remained ctDNA-positive through follow-up. Of the 2 patients not detected by ctDNA, one had a small local recurrence only (now resected) and the other had three primary tumours. None of the 31 non-relapsing patients were ctDNA-positive at any time point (n=142). Metastatic relapse was predicted by Signatera with high accuracy and a lead time of up to 2 years (median=9.5 months).

Conclusions:

The use of a scalable patient-specific ctDNA-based validated workflow detects breast cancer recurrence ahead of clinical detection. Accurate and earlier prediction by ctDNA analysis could provide a means of monitoring breast cancer patients in need of second-line salvage adjuvant therapy in order to prevent overt life-threatening metastatic progression.

Citation Format: Coombes RC, Armstrong A, Ahmed S, Page K, Hastings RK, Salari R, Sethi H, Boydell A-R, Shchegrova SV, Fernandez-Garcia D, Gleason KL, Goddard K, Guttery DS, Assaf ZJ, Balcioglu M, Moore DA, Primrose L, Navarro SL, Aleshin A, Rehman F, Toghill BJ, Louie MC, Zimmermann BG, Lin C-HJ, Shaw JA. Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence [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 P4-01-02.