bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-13-02: BRCA1/2 founder mutations among high-risk HBOC patients from Northeast of Brazil
Authors: Nascimento Ivana L , Felix Gabriela ES , Sandes Camila A , Machado-Lopes Taisa B , Bomfim Thais F , Meyer Roberto , Romeo Maura , Toralles Betania , Sandes Kiyoko A
Published: May 2015

Background: Genetic susceptibility to Hereditary Breast and Ovarian Cancer (HBOC) syndrome could be test by the screening of BRCA1 and BRCA2 genes. Thus, knowing that each population has its degree of heterogeneity and the Brazilian population is one of the most heterogeneous of the world, we aimed to verify the frequency of BRCA1/2 founder mutations in high-risk HBOC patients from Bahia, the biggest State of the Northeast of Brazil.

Methods: It was analyzed the DNA of 98 unrelated high-risk HBOC patients, considering the criteria of NCCN v.1.2010. These patients were tested for the next founder mutations: BRCA1 c.211A>G (Galician), BRCA1 943ins10 (African), BRCA1 3450del4 (Hispanic) and BRCA2 c.5946_5946delT (Portuguese) by sequencing or PCR/RFLP. All positive results were confirmed by two sequencing reactions. The genetic ancestry was analyzed with a panel of 10 ancestry informative markers (AIMs). The clinical and epidemiological data were collected during the genetic counseling and were analyzed in Epi InfoTM 7, while the frequency of the AIMs was analyzed in GENEPOP, and in ADMIX95 the genetic admixture was estimated.

Results: All patients had personal and/or familial history of breast and/or ovarian cancer. Most of the patients self-reported as mulatto (61.23%), followed by black (21.43%), white (10.20%) and others (7.14%). The African, Amerindian and European ancestry contribution estimated were 35.33%, 11.31% and 53.35% respectively (R2 = 0.998). Two mutations were detected the BRCA1 3450del4 in five patients (4.90%) and the BRCA1 c.211A>G in two patients (2.04%). All patients with these mutations were from State of Bahia and self-reported as mulatto or white. Any carrier declared as Spanish descendant.

Conclusion: Although the Portuguese settled Brazil, here it was observed that this population seems to have high Spanish ancestry contribution, due to the high frequency of the BRCA1 3450del4 and c.211A>G (6.94%). It is also interestingly the absence of BRCA1 943ins10, because the State of Bahia has the higher rate of African-descendants in Brazil and most of the patients exhibited these physical traits (mulatto and black, 82.65%). Thus, high-risk patients from that region of Brazil could be screening first for the BRCA1 3450del4 and BRCA1 c.211A>G, where it has a founder effect.

Citation Format: Ivana L Nascimento, Gabriela ES Felix, Camila A Sandes, Taisa B Machado-Lopes, Thais F Bomfim, Roberto Meyer, Maura Romeo, Betania Toralles, Kiyoko A Sandes. BRCA1/2 founder mutations among high-risk HBOC patients from Northeast of Brazil [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-13-02.
Abstract P4-14-04: United States breast cancer mortality trends in young women according to race
Authors: Ademuyiwa Foluso O , Gao Feng , Hao Lin , Morgensztern Daniel , Aft Rebecca L , Ma Cynthia X
Published: May 2015

Purpose

Studies have shown that there is a negative prognostic impact of young age at diagnosis on clinical outcome in women with breast cancer (BC). We sought to determine if there is a differential effect of race in this high-risk population of women and examined mortality trends according to race and diagnosis age.

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) program 1990-2009, women diagnosed with invasive BC under the age 50 were identified. Clinicopathologic characteristics, overall survival, and BC specific survival rates were compared between racial groups. After adjustments for stage, ER, PR, histology, age, diagnosis year, tumor size, nodal status, and grade, multivariate logistic regression analyses determined the risk-adjusted likelihood of survival for whites and blacks. Annual hazard rates (HR) of BC deaths after diagnosis according to race and calendar period, and adjusted relative hazards of death for white and black women stratified by age at diagnosis were computed.

Results

Overall, 162,976 women were identified, including 126,573 whites (77.7%), 20,405 blacks (12.5%), and 15,998 of other races (9.8%). At a median follow-up of 85 months, five year disease specific survival rates were 90.1% for whites, and 79.3% for blacks. During the study period, the annual HR for death in whites decreased by 26% at 5 years after diagnosis, in contrast to the rates in blacks women decreasing by only 19%. With 1990 as referent, adjusted relative hazards for death in 2005 for white and black women <40 years were 0.55 (95% CI 0.46-0.66) and 0.68 (95% CI 0.49-0.93) respectively. In whites and blacks ≥40, 2005 hazards were 0.53 (95% CI 0.47-0.60) and 0.78 (95% CI 0.61-0.99).

Conclusion

Among young women diagnosed with BC, blacks have a worse outcome than whites. Mortality declines in both racial groups have been observed over time, although more rapid gains have occurred in whites. Emphasis should be placed on improving outcomes for young BC patients.

Citation Format: Foluso O Ademuyiwa, Feng Gao, Lin Hao, Daniel Morgensztern, Rebecca L Aft, Cynthia X Ma. United States breast cancer mortality trends in young women according to race [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-04.
Abstract P4-15-06: Correlation between ERBB2 mRNA levels, HER2-dependence and susceptibility to trastuzumab in human breast cancer
Authors: Tagliabue Elda , Regondi Viola , De Cecco Loris , Pupa Serenella M , Campiglio Manuela , Carcangiu Maria Luisa , Ménard Sylvie , Triulzi Tiziana
Published: May 2015

While results thus far demonstrate the clinical benefit of trastuzumab in breast cancer, some patients do not respond to this reagent. Identifying a robust clinical or molecular predictor of adjuvant trastuzumab benefit has proven challenging and even the most obvious candidate biomarker for a predictor of trastuzumab benefit, HER2 expression as assessed by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH), has proven to be surprisingly ambiguous in realizing benefit from the antibody. Results of a recent study that profiled expression of select genes in archived formalin-fixed, paraffin-embedded (FFPE) tumor blocks from a randomized study of breast cancer patients treated with adjuvant trastuzumab support a relationship between ERBB2/ESR1 mRNA levels and trastuzumab sensitivity. Based on that observation, we conducted whole-genome profiling by DASL technology of archival FFPE tumor blocks from 53 HercepTest 3+/2+ FISH-positive patients treated with adjuvant trastuzumab in our Institute; 308 genes were significantly associated with relapse-free survival by Cox proportional hazard model (α<0.005; permutation test p<0.01). We then developed a relapse risk 41-gene classifier (TRAR) able to discriminate cases mainly according to ERBB2 and ESR1 mRNA expression levels and to predict tumor relapse in both trastuzumab adjuvant and neoadjuvant settings. No correlation was found between ERBB2 mRNA and HER2 protein expression (the latter assessed by IHC on FFPE tumor sections using serial dilutions of anti-HER2 antibody), nor did HER2 protein expression correlate with relapse risk in these tumors. Analysis of HER2-amplified breast carcinoma cell lines revealed higher levels of ERBB2 mRNA in oncogene-addicted than in non-addicted cells in correlation with HER2 activation assed by Western blot but not with total HER2 protein amount. Moreover, ERBB2 mRNA expression levels in HER2-amplified breast carcinoma cells correlated with trastuzumab-mediated cellular cytotoxicity (ADCC) in vitro (r=0.96, p=0.038), whereas no correlation was found between ADCC and membrane-associated HER2.

Together, our findings strongly suggest that ERBB2 mRNA, but not protein levels, mirror HER2 activity and thus oncogene addiction of tumor cells and susceptibility to trastuzumab in amplified HER2-positive tumors.

Supported by AIRC.

Citation Format: Elda Tagliabue, Viola Regondi, Loris De Cecco, Serenella M Pupa, Manuela Campiglio, Maria Luisa Carcangiu, Sylvie Ménard, Tiziana Triulzi. Correlation between ERBB2 mRNA levels, HER2-dependence and susceptibility to trastuzumab in human breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-06.
Abstract P4-15-13: CDK8 inhibition potentiates anti-ER and anti-HER2 therapies in breast cancer
Authors: McDermott Martina S , Lim Chang-uk , Chen Mengqian , Chumanevich Alexander , Catroppo James F , Gyorffy Balazs , Oliver David , Roninson Igor B , Broude Eugenia V
Published: May 2015

CDK8, along with its paralog CDK19, is a cyclin dependent kinase which, in contrast to other members of the CDK family does not regulate cell cycle progression. CDK8 acts as a pleiotropic transcription regulator potentiating the induction of transcription by several transcription factors. Immunohistochemical staining of breast tissue arrays and bioinformatics analysis of gene expression microarray data of breast cancer patients revealed that CDK8 is overexpressed in breast cancer and that higher CDK8 expression correlates with the failure of systemic therapy. Small-molecule selective inhibitors of CDK8 and CDK19 (Senexin A and Senexin B) inhibited the mitogenic effects of estrogen and estrogen-dependent transcription in estrogen receptor (ER)+ breast cancer cell lines. CDK8/19 inhibitors had a cytostatic effect on different ER+ cell lines, and this growth inhibition was synergistic with the effect of the anti-estrogen fulvestrant, particularly in ER+ cell lines resistant to estrogen deprivation. Some of the ER+ cell lines sensitive to CDK8/19 inhibition also express HER2, and therefore we tested CDK8/19 inhibitors in combination with the HER2 and EGFR tyrosine kinase inhibitor lapatinib and an anti-HER2 monoclonal antibody, a biosimilar of trastuzumab. CDK8/19 inhibition produced a synergistic decrease in cell growth with both HER2 inhibitors; this effect was especially pronounced with a trastuzumab biosimilar. Surprisingly, the synergistic effect with HER2 inhibitors was observed in both ER+ HER2+ and ER-HER2+ cell lines, suggesting an effect on a HER2-complementing molecular target other than ER. Interestingly, CDK8/19 inhibition also synergized with trastuzumab biosimilar in a breast cancer cell line that exhibits innate resistance to trastuzumab, suggesting that CDK8/19 inhibition can overcome trastuzumab resistance in breast cancer. These results suggest that combining anti-estrogen and anti-CDK8 therapy may be more effective than conventional hormone therapy for ER positive breast cancer and that combining anti-HER2 and anti-CDK8 therapy is a rational potential treatment for HER2+ breast cancer, regardless of ER status or sensitivity to trastuzumab.

Citation Format: Martina S McDermott, Chang-uk Lim, Mengqian Chen, Alexander Chumanevich, James F Catroppo, Balazs Gyorffy, David Oliver, Igor B Roninson, Eugenia V Broude. CDK8 inhibition potentiates anti-ER and anti-HER2 therapies in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-13.
Abstract P4-15-14: Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression
Authors: Verheijden Gijs , Beusker Patrick , Ubink Ruud , Lee Miranda van der , Groothuis Patrick , Goedings Peter , Egging David , Timmers Marco , Dokter Wim
Published: May 2015

SYD985 is a novel anti-HER2 antibody-drug conjugate (ADC) in development for breast cancer. The ADC consists of three parts: i) the monoclonal antibody trastuzumab, ii) a linker that can be cleaved by tumor-resident proteases at the dipeptide valine-citrulline (vc) motif, and iii) the prodrug seco-DUocarmycin-hydroxyBenzamide-Azaindole. The average ‘drug to antibody ratio’ (DAR) of this ADC, also named trastuzumab vc-seco-DUBA, is ∼2.8. After antibody-mediated binding of SYD985 to its molecular target HER2 on the surface of tumor cells, the ADC is internalized. Subsequently, the active duocarmycin is released and binds to DNA in the minor groove, followed by alkylation of the DNA and killing of the tumor cells.

In vitro and in vivo experiments were performed to (directly) compare various pharmacodynamic and pharmacokinetic properties of SYD985 with those of the most progressed (marketing-approved) HER2-targeting ADC, i.e. ado-trastuzumab emtansine (T-DM1). T-DM1 is currently indicated for second line treatment of breast cancer patients overexpressing HER2 tumor tissue.

In in vitro experiments, SYD985 shows potencies similar to T-DM1 in cell lines expressing HER2 at high levels (IHC HER2 3+), whereas SYD985 is significantly more potent compared to T-DM1 in cell lines expressing low HER2 levels (IHC HER2 2+ or 1+). In line with these results, SYD985 has superior efficacy compared to T-DM1 in xenograft models in which patient-derived breast cancer tumor tissue with low HER2 levels (IHC HER2 2+ or 1+/FISH-) have been used.

Pharmacokinetic experiments (in vitro and in vivo) have revealed that whereas in mice SYD985 has limited stability, in cynomolgus monkey SYD985 is very stable. Excellent stability in vitro is also observed in human plasma. Moreover, after i.v. administration of SYD985 in the cynomolgus monkey the amount of free toxin (DUBA) detected in the monkey plasma is many-fold lower than levels reported for the toxin (DM1) released from T-DM1.

Resuming, the preclinical data of SYD985 support clinical studies to investigate whether SYD985 has benefit in cancer patients with moderate or even low HER2 levels of the tumor tissue.

Citation Format: Gijs Verheijden, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Patrick Groothuis, Peter Goedings, David Egging, Marco Timmers, Wim Dokter. Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-14.
Abstract P4-15-22: The ASCO/CAP guideline update for HER2 testing increases the number of breast cancer patients eligible for HER2-targeted therapy
Authors: Giacomazzi Juliana , Hartmann Carolina R , Paskulin Diego D , Rivero Luis Fernando , Caleffi Maira , Pasqualotto Alessandro C , Graudenz Marcia S , Rosa Daniela D
Published: May 2015

Background: The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) published, in Nov/2013, the interpretive guidelines for HER2 testing of breast cancer patients. This aimed to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. The former version of these criteria was written in 2007. Objectives: to compare the HER2 immunohistochemical (IHC) analysis using the 2007 versus 2013 algorithms in a cohort of breast cancer cases diagnosed in a single institution in Southern Brazil. The cases were previously classified as HER2 1+ or 2+, using the 2007 criteria. Methods: the sample included 100 invasive breast cancer cases. The HercepTest (Dako, Denmark) was used for determination of HER2 expression. The HER2 testing was analyzed independently by two pathologists. The FISH analysis was done using a HER2/D17Z1 probe set. Preliminary Results: The HER2 IHC interpretation changed in 11/69 (15.9%) cases: 8.7% negative or equivocal cases by the 2007 guidelines were positive by the 2013 classification and 7.2% of HER2 1+ cases became equivocal (p<0.001; x2 test). The FISH analyses are ongoing. Conclusion: The 2013 ASCO/CAP guidelines resulted in less negative cases and in more equivocal (requiring reflex testing) and positive tests. Applying the ASCO/CAP 2013 guidelines resulted in a significantly increase of breast cancer patients eligible for HER2-targeted therapies.

Citation Format: Juliana Giacomazzi, Carolina R Hartmann, Diego D Paskulin, Luis Fernando Rivero, Maira Caleffi, Alessandro C Pasqualotto, Marcia S Graudenz, Daniela D Rosa. The ASCO/CAP guideline update for HER2 testing increases the number of breast cancer patients eligible for HER2-targeted therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-22.
Abstract P5-02-12: Concordance between semiquantitative immunohistochemical assay and oncotype DX RT-PCR assay for estrogen and progesterone receptors
Authors: Novas Patricia , Galve Elena , Fernández Sara , Sala Maria Ángeles , Arévalo Alberto , Arango Juan , López de San Vicente Borja , Fernández Seila , Zumárraga Ane , Martínez del Prado Purificación
Published: May 2015

Introduction: Estrogen receptor (ER) and progesterone receptor (PR) expression are generally determined by semiquantitative immunohistochemistry (IHC) as recommended in the clinical practice guidelines of the American Society of Clinical Oncologists. This method may be subject to variability because of differences in fixation, ER antibody clones, as well as to immunostain interpretation and use of arbitrary cut-off points. Materials and methods: We identified 72 breast cancer cases at Basurto University Hospital from 1 September 2012 to 31 May 2014 that have been analyzed by Oncotype DX with reporting on ER/PR expression levels by RT-PCR (Genomic Health Inc, Redwood City, CA). According to the company’s report, a tumor is considered as ER positive with expression units of >=6.5 and PR positive with expression units of >=5.5. Oncotype DX is a commercial assay that predicts tumor recurrence in node-negative ER-positive breast cancers. It is a reverse transcription-polymerase chain reaction (RT-PCR) based assay that analyzes the expression of 21 genes (16 cancer-related and 5 control genes) to provide a distant disease recurrence score ranging from 0 to 100. At our institution, hormone receptors by IHC were analyzed on corresponding surgery breast specimens at the time of initial diagnosis. They were evaluated by IHC on formalin-fixed paraffin-embedded tissue, between 8-72 hours. ER was assessed using Roche antibody clone SP1 and PR was assessed using antibody clone 1E2. Percentage of positive nuclei was determined by visual microscopic estimation: <1 negative and ≥1 positive. We compared our semiquantitative method of reporting ER and PR status based on IHC to the RT-PCR hormone receptor results from Genomic Health. Results: There was 100% concordance between IHC and the RT-PCR assay for estrogen receptor status. PR findings between IHC and Oncotype Dx revealed a lower concordance (82%) than for ER. RT-PCR was negative in 10 (14%) cases in which IHC was positive. Pearson correlation coefficient for PR was 0.313. Although our results demonstrated high concordance between IHQ and Oncotype Dx for ER, our data showed poor concordance for PR.

Citation Format: Patricia Novas, Elena Galve, Sara Fernández, Maria Ángeles Sala, Alberto Arévalo, Juan Arango, Borja López de San Vicente, Seila Fernández, Ane Zumárraga, Purificación Martínez del Prado. Concordance between semiquantitative immunohistochemical assay and oncotype DX RT-PCR assay for estrogen and progesterone receptors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-02-12.
Abstract P5-04-14: Decreased functions of natural killer cells in peripheral blood of advanced triple negative breast cancer patients
Authors: Park In Hae , Kong Sun-Young , Kang Joo Hyun , Mo Hye Jin , Kim Tae Sik , Lee Keun Seok , Ro Jungsil
Published: May 2015

Background : Natural killer (NK) cells are a major player in innate immune response. Two distinct NK cell subsets with different functions as the strongest cytotoxic activity (CD56dimCD16+) or cytokine production (CD56brightCD16+/-) have been known. In this study, we evaluated the phenotypic and functional difference of NK cells in peripheral blood (pB) from the patients who had advanced triple negative (TN) breast cancer compared to healthy controls.

Methods : We enrolled advanced triple negative (TN) breast cancer patients treated at the National Cancer Center, Korea between March 2012 and March 2014. Healthy controls who visited for health screening were recruited at the same time period and peripheral blood (pB) samples were collected. In patient groups, pB was sampled either prior to the initiation or during the courses of chemotherapy. Then, patients were retrospectively classified into two groups as follows; non-responders (the group A) and responders (the group B) to the treatment. NK cells were isolated from peripheral blood mononuclear cells (PBMC) and analyzed based on their expression of CD56 and CD16. We looked at cytotoxic activity of pB NK cells against K562 cell line and measured CD107a expression as a parameter of NK cell activation.

Results : The absolute numbers of lymphocytes and NK cells per cubic millimeter of pB were similar among healthy controls (N=24), the group A (N=16), and the group B (N=21). There was no significant difference in the proportion of pB NK cell subsets among three groups except CD56brightCD16+/- subset which was significantly higher in the group B compared to healthy controls (P=0.0014). Even in the presence of similar proportions of NK subsets, the activities of CD56dimCD16+ NK cells measured by CD107a expression were significantly lower both in the group A (P=0.0023) and in the group B (P=0.0127) compared with those of control group. The activities of CD56dimCD16+ NK cells were not different between group A and B. In the case of CD56brightCD16+/- NK cells, CD107a positivity was significantly lower in the group A compared with controls (P=0.0068) and group B (P=0.0465).

Conclusions : Our data suggested that cytolytic functions of NK cells were significantly decreased in advanced TN breast cancer patients compared with those of healthy controls despite a similar proportion of NK cell subsets in pB.

Citation Format: In Hae Park, Sun-Young Kong, Joo Hyun Kang, Hye Jin Mo, Tae Sik Kim, Keun Seok Lee, Jungsil Ro. Decreased functions of natural killer cells in peripheral blood of advanced triple negative breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-14.
Abstract P5-07-01: Granulin, a novel STAT3-interacting protein, promotes breast cancer tumorigenicity
Authors: Yeh Jennifer E , Kreimer Simion , Walker Sarah R , Richardson Andrea , Ivanov Alexander R , Frank David A
Published: May 2015

Since the neoplastic phenotype of a cell is largely driven by its gene expression patterns, increasing attention is focused on transcription factors that regulate critical mediators of tumor formation and metastatic progression like the oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). Whereas normal cells have transient activation of STAT3 due to tight control by negative regulators, cancer cells frequently have inappropriate constitutive activation of STAT3 which drives increased expression of genes involved in tumorigenesis. However, little is known about proteins that interact with STAT3 to modulate its function. To identify novel STAT3-interacting proteins, we performed liquid chromatography tandem mass spectrometry-based profiling of STAT3-containing complexes immunoprecipitated from the triple-negative breast cancer cell lines MDA-MB-468 and SUM159PT, which have constitutively active STAT3. We identified granulin (GRN) as a novel STAT3-interacting protein and validated the STAT3-GRN interaction in breast cancer cells by co-immunoprecipitation. To investigate the functional effect of GRN on STAT3 activity, we silenced GRN using small interfering RNA. We found that GRN was necessary for constitutive and maximal cytokine-induced STAT3 transcriptional activity in breast cancer cells. GRN modulated cytokine-induced STAT3 function by enhancing STAT3 DNA binding and increasing the time-integrated amount of STAT3 activation and nuclear translocation. Silencing GRN mirrored the effect of silencing STAT3 on reducing the viability, clonogenesis, and migratory capacity of triple-negative breast cancer cells. Furthermore, GRN mRNA levels were significantly and positively correlated with STAT3 gene expression signatures indicative of STAT3 activation as well as with reduced overall survival in breast cancer patients. These studies used a proteomics approach to identify GRN as a novel STAT3 interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer.

Citation Format: Jennifer E Yeh, Simion Kreimer, Sarah R Walker, Andrea Richardson, Alexander R Ivanov, David A Frank. Granulin, a novel STAT3-interacting protein, promotes breast cancer tumorigenicity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-01.
Abstract P5-09-02: The CYP19 RS4646 polymorphism is related to the prognosis of stage I–II and operable stage III breast cancers
Authors: Shao Xiying , Wang Xiaojia , Zheng Yangbing , Huang Ping , Huang Jian
Published: May 2015

Background: Aromatase, encoded by the CYP19 gene, catalyzes the final step of the conversion of androgens to estrogens. In premenopausal women, estrogen is mainly produced by the ovary, while in postmenopausal women, aromatization of androgen in extragonadal tissue, for example, adipose tissue, is the main source. Given the critical role of CYP19 in estrogen synthesis and the association of clinical outcome with rs4646 polymorphism, we investigated the clinical relevance of CYP19 rs4646 genotypes in early breast cancer.

Methods: Genotype for CYP19 rs4646 variants was performed on 406 Chinese women with early breast cancer. Associations were examined between rs4646 genotypes with histopathological characteristics and disease-free survival.

Results: In patients younger than 50 years, women who are homozygous for the minor allele (AA) have a longer disease-free survival (DFS)compared with those carrying the major allele(CC or AC) (87 months versus 48.7 months; HR 0.560; 95CI 0.318-0.985; P =0.041). This differences was further demonstrated by a multivariate analysis (HR 0.456; 95CI 0.249-0.836; P=0.011). Conversely, the same variants(AA) were found to be associated with a poorer DFS in women with age above 50 years (AA versus AC or CC: 38.9months versus 79.7 months; HR 2.758; 95% CI: 1.432-5.313; P=0.002). Furthermore, the differences was proved by the COX proportional hazards model (HR 2.983; 95CI 1.494-5.955; P=0.002).

Conclusions: The present study indicates that CYP19 rs4646 polymorphism is associated with DFS in early breast cancer and that the prognosis index of the homozygous for the minor allele (AA) may depend on circulating estrogens levels due to the different age. The founding is novel, if confirmed in a larger prospective independent cohort, rs4646 genotypes may provide useful information for routine management in breast cancer.

Citation Format: Xiying Shao, Xiaojia Wang, Yangbing Zheng, Ping Huang, Jian Huang. The CYP19 RS4646 polymorphism is related to the prognosis of stage I–II and operable stage III breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-09-02.
Abstract P5-10-17: Evaluation of PgR status by immunohistochemistry may be inferior to PgR results by Oncotype DX for assessing the recurrence risk in ER+/HER2- breast cancer with low or intermediate tumor proliferation
Authors: Sinn Peter , Kriegsmann Mark , Felten Ute , Wacker Jürgen , Schneeweiss Andreas , Varga Zsuzsanna
Published: May 2015

Background: Loss of progesterone receptor expression is known to be a predictor of Luminal-B subtype, and is of independent prognostic significance in luminal type breast cancer. However, the threshold of PgR status in IHC has been subject to debate, and the PgR status as reported by IHC not infrequently is at variance with the PgR result as reported by the Oncotype DX (ODX) assay.

Methods: We retrospectively reviewed tumor IHC and ODX data from resection specimens with ER+/HER2- breast cancer, and low to intermediate Ki-67 proliferation rates (Ki-67 < 30%). A total of 74 specimens were re-analyzed, all from resection specimens that had been selected for ODX assay for the purpose of planning of adjuvant chemotherapy, from two institutions (Univ. Heidelberg, Germany, and Univ. Zurich, Switzerland). PgR expression of < 10% using IHC (clone PgR636, Ventana and Dako systems) or PgR values of < 5,5 in ODX assay were considered negative.

Results: All cases were positive for ER by IHC and ODX, and 20% were negative for PgR by ODX assay. This compared to only 8% of negativity by IHC, but all except one case negative for PgR by IHC were also correctly identified as PgR negative by ODX. Median ODX recurrence score (RS) was 35 for PgR negativity by ODX assay, as compared to 30 for negative PgR status by IHC. For positive PgR status, median RS was calculated as 15 vs. 17 by ODX vs. IHC. Risk categories by ODX were high (RS >= 31) in 9 cases with negative PgR status by ODX, but only 3 of these high risk cases were negative for PgR by IHC. Median Ki-67 values were 22.5 for PgR negative cases by ODX as compared to 15 for PgR negative cases by IHC. Similar results were obtained when a higher PgR threshold of 20% was applied to IHC results.

Conclusions: In luminal type breast cancers, the evaluation of PgR status by IHC may underestimate the proportion of PgR negative cases and did not identify most cases of tumors with a high risk of recurrence. This may be caused by an overly high sensitivity of PgR status in routine automated immunohistochemistry.

Citation Format: Peter Sinn, Mark Kriegsmann, Ute Felten, Jürgen Wacker, Andreas Schneeweiss, Zsuzsanna Varga. Evaluation of PgR status by immunohistochemistry may be inferior to PgR results by Oncotype DX for assessing the recurrence risk in ER+/HER2- breast cancer with low or intermediate tumor proliferation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-17.
Abstract P5-13-02: The beliefs, knowledge, understanding, attitudes and treatment access to breast cancer amongst rural women in Northern Nigeria
Authors: Tagbarha Malcolm O
Published: May 2015

Goal: The goal of this study is to ascertain the beliefs, knowledge, understanding, attitudes and treatment access to breast cancer among rural women in Nigeria.

Background: Breast cancer has become a popular topic in recent years with several thousands of women diagnosed to be positive every year. The availability of care/treatment upon early detection is key to survival.

Methods: An interview guide was designed specifically for this study in which 200 rural women in Northern Nigeria, age 45 and over took part in. It contained questions about beliefs, knowledge, understanding and attitudes about Breast Self-Examination (BSE), Clinical Breast Examination (CBE) and mammogram. In addition, questions assessing the variables of the Health Belief Model and health motivations also were included. The data were obtained during face-to-face interviews in the primary language of the participating woman. The interviews were transcribed and translated into English.

Results: Out of the 200 women who participated, only 1% two (2) of the participants practiced BSE monthly, 8% had undergone at least one CBE during their lives, and 91% had never had a mammogram. There were little or no access to treatment even at early detection in these rural areas causing thereby vulnerability to loss of life. Majority of these rural women (95%) said they knew little or nothing about breast cancer. While 15% of the women said detecting cancer early was important, only 3% reported that cancer could be cured. Age, education, or mother tongue showed no statistically significant relationship with the breast health practice scores. However, proficiency with the English language (p = 0.009) and number of years exposed to awareness and education (p = 0.009) had a significant relationship with the breast health practice scores. The significant explanatory factor for the variable breast health practices was a cue to action (p = 0.009).

Conclusions: The level of awareness and treatment access to breast cancer amongst Northern Nigeria’s rural women is extremely low thereby making them not to engage in screening and/or detection practices. This alarming situation calls for urgent intervention of medical/health organizations to provide immediate breast cancer awareness, screening and care so as to reduce incidences or threat at early detection.

Citation Format: Malcolm O Tagbarha. The beliefs, knowledge, understanding, attitudes and treatment access to breast cancer amongst rural women in Northern Nigeria [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-13-02.
Abstract P5-19-12: Subgroup analysis on efficacy in the routine treatment - Results of the 2nd interim analysis of BRAWO, the non-interventional trial "Breast Cancer Treatment with Everolimus and Exemestane for HR+ Women"
Authors: Jackisch Christian , Grischke Eva-Maria , Schneeweiss Andreas , Decker Thomas , Uleer Christoph , Förster Frank , Tomé Oliver , Wimberger Pauline , Kurbacher Christian M , Mueller Bettina , Harbeck Nadia , Mundhenke Christoph , Kuemmel Sherko , Muth Mathias , Kreuzeder Julia , Bloch Wilhelm , Tesch Hans , Lüftner Diana , Schütz Florian , Fasching Peter A
Published: May 2015

Introduction

BRAWO is a German non-interventional study of 3000 patients (pts) with advanced or metastatic, hormone-receptor-positive, HER2-negative breast cancer treated with everolimus (EVE) and exemestane (EXE). We report results of the 2nd preplanned interim analysis (IA) with a data cut-off on 8th July 2014.

Methods

BRAWO collects data on the routine clinical treatment with EVE and EXE at about 400 sites. Main objectives are to extend the knowledge on a) the efficacy in the clinical routine and the impact of physical activity on efficacy and quality of life, b) prophylaxis and management of stomatitis, and c) the sequence of therapy in the clinical routine. The 2nd IA was defined to take place 12 months after the inclusion of the 500. patient into the documentation.

Results

Efficacy data will be reported for the first 500 documented pts. Apart from data on the total study population we will present the PFS results for subgroups including pts with or without prior EXE therapy, with or without prior chemotherapy for the advanced setting, with or without visceral metastasis and with regard to the line of treatment in the advanced setting and the extent of physical activity. The respective summary of adverse events for these patients will be presented as well as results on treatment compliance and dosing. Baseline characteristics and medical history as well as insights into treatment sequences before EVE and EXE will further be shown for all enrolled patients with valid baseline documentation (approx. 1200).

Conclusion

This subgroup analysis will provide insights into the treatment efficacy in the clinical routine and will add to a more comprehensive understanding of the treatment with EVE/EXE.

Citation Format: Christian Jackisch, Eva-Maria Grischke, Andreas Schneeweiss, Thomas Decker, Christoph Uleer, Frank Förster, Oliver Tomé, Pauline Wimberger, Christian M Kurbacher, Bettina Mueller, Nadia Harbeck, Christoph Mundhenke, Sherko Kuemmel, Mathias Muth, Julia Kreuzeder, Wilhelm Bloch, Hans Tesch, Diana Lüftner, Florian Schütz, Peter A Fasching. Subgroup analysis on efficacy in the routine treatment - Results of the 2nd interim analysis of BRAWO, the non-interventional trial "Breast Cancer Treatment with Everolimus and Exemestane for HR+ Women" [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-12.
Abstract P5-20-04: Autophagy promotes escape from PI3K inhibition in ER+ breast cancer
Authors: Yang Wei , Miller Todd W
Published: May 2015

PI3K inhibitors have shown promise for the treatment of ER+ breast cancers. Autophagy has been suggested to promote resistance to PI3K inhibitors. Interestingly, cancer cells often exhibit basal levels of autophagy, which is thought to serve as a mechanism to manage oxidative stress and remove damaged organelles (e.g., mitochondria). Pharmacodynamic analysis of the orally available pan-PI3K inhibitor GDC-0941 at low (100 mg/kg) and high (800 mg/kg) doses, and 2 low doses administered 12 hours apart (BID), in combination with fulvestrant in mice bearing MCF-7 xenografts revealed that treatment induced accumulation of LC-3 II (marker of autophagy) after 24-48 h. In ER+ breast cancer cells cultured in hormone-depleted medium, PI3K inhibition gradually induced apoptosis while increasing LC-3 II. Autophagy promotes glucose metabolism, and PI3K activation is a major driver of glucose uptake. We thus hypothesized that inhibition of autophagy will potentiate the anti-tumor effects of PI3K inhibition by suppressing glucose metabolism.

Chloroquine (CQ) is an anti-malarial drug that inhibits autophagy in mammalian cells by an unknown mechanism. CQ inhibited proliferation and autophagy in ER+ breast cancer cells in vitro. CQ treatment potentiated GDC-0941-induced inhibition of cell proliferation and promotion of apoptosis in growth conditions (10% FBS) with or without fulvestrant, and in hormone-depleted conditions (10% DCC-FBS). CQ treatment increased PI3K inhibitor-induced mitochondrial membrane depolarization, suggesting that this drug combination engages an intrinsic apoptotic pathway. PI3K inhibition also induced autophagy in fulvestrant-resistant MCF-7/FR and CAMA-1/FR cells. CQ increased GDC-0941-induced apoptosis in MCF7/FR and CAMA-1/FR cells, offering combined targeting of PI3K and autophagy as a promising therapeutic strategy for the treatment of anti-estrogen resistant breast cancer.

Mice bearing ZR75-1 xenografts are currently being treated with vehicle, CQ (2 mg/day via drinking water), 800 mg/kg GDC-0941 QW, or the combination. Thus far, single-agents treatments significantly inhibit tumor growth. However, the drug combination has not shown synergistic effects in vivo. Analysis of different doses and schedules of GDC-0941 plus CQ, with or without anti-estrogen treatment, is ongoing.

Citation Format: Wei Yang, Todd W Miller. Autophagy promotes escape from PI3K inhibition in ER+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-20-04.
Abstract P5-21-09: Oncologist treatment choices in patients with early stage invasive lobular breast carcinoma - a survey
Authors: Jacobs Carmel , Clemons Mark , Ibrahim Mohamed FK , Addison Christina , Caudrelier Jean-Michel , Graham Ian D , Hutton Brain , Arnaout Angel
Published: May 2015

Introduction: Invasive lobular carcinoma (ILC) is common and accounts for 5-15% of all breast cancers. ILC has distinct clinical and histological features that separate it from invasive ductal carcinoma (IDC) with regards to its breast imaging characteristics, patterns of recurrence and sensitivity to systemic therapy. ILC presents challenges to the physician in many aspects of local-regional and systemic therapy choices. We surveyed breast cancer physicians on their beliefs and practice patterns on issues around the management of ILC.

Methods: A questionnaire was developed and circulated electronically using a modified Dillman technique to surgical, radiation, and medical oncologists across Canada and Ireland.

Results: The questionnaire was completed by 91 of 429 physicians (21% response rate). Response rate by specialty was 25/69 (36%), 21/54 (41%) and 45/306 (13%) for surgical, radiation and medical oncologists respectively. Most surgeon responders (77%) would feel "uncomfortable making treatment decisions for ILC with a mammogram alone" and 100% would be "more comfortable with an MRI". Although 55% reported treating ILC as they would IDC, 22% of surgeons will purposefully obtain larger gross margins intra-operatively. Some radiation oncologists believe ILC is an independent risk factor for local-regional recurrence after breast conserving surgery (49%), and after mastectomy (29%). 33% of radiation oncologists would offer radiation therapy after mastectomy specifically because of the ILC subtype even in the absence of usual indications for radiotherapy. Most medical oncologists treat ILC comparably to IDC with the factors having the largest influence on systemic treatment decisions being tumour stage, hormone receptor status and HER-2 status. 51% of medical oncologists treat ILC with adjuvant chemotherapy as they do for IDC at least ‘most of the time’, while 40% use neoadjuvant chemotherapy as frequently as they do for IDC at least ‘most of the time’. 75% of medical oncologists manage the hormonal treatment of ILC as they do IDC ‘most of the time’ or ‘always’.

Conclusions: There remains significant clinical equipoise in the local-regional and systemic management of ILC. This survey has demonstrated wide variations in both beliefs and practices of management for ILC. Clinical guidance, developed on clinical trials specifically assessing the management of ILC, is required.

Citation Format: Carmel Jacobs, Mark Clemons, Mohamed FK Ibrahim, Christina Addison, Jean-Michel Caudrelier, Ian D Graham, Brain Hutton, Angel Arnaout. Oncologist treatment choices in patients with early stage invasive lobular breast carcinoma - a survey [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-09.
Abstract P6-01-11: The neuronal protein sortilin is expressed in aggressive breast cancers and participates in tumor cell growth and invasion
Authors: Pundavela Jay , Roselli Severine , Demont Yohann , Faulkner Sam , Attia John , Keene Sheridan , Walker Marjorie M , Hondermarck Hubert
Published: May 2015

The membrane protein sortilin is involved in intracellular trafficking and has emerged as a key player in the regulation of neuronal viability and function. Few studies have suggested that sortilin may also be implicated in cancer, but its expression in human tumors and potential value as a therapeutic target is unknown. In this study, the level of sortilin was analyzed in a series of 318 clinically annotated breast cancers and 53 normal adjacent tissues by immunohistochemistry. Sortilin was specifically localized in epithelial cells and was detected in 65% of cancers compared to 46% of normal tissues (p=0.0088). Sortilin was detected in 79% of invasive ductal carcinomas compared to only 54% of invasive lobular carcinomas (p<0.0001). Interestingly, sortilin was associated with lymph node involvement (p=0.0093), suggesting a relationship with metastatic potential and poor outcome. In Log-Linear modeling, two-way analyses confirmed the association of sortilin with histological type (ductal vs. lobular invasive carcinomas) and lymph node invasion (p=0.002 and p=0.096 respectively). In vitro, sortilin was detected in a range of cancer cell lines using RTPCR and Western-blotting. Functional investigation using RNA interference revealed that a decrease in sortilin level in the highly metastatic breast cancer cell line MDA-MB-231 resulted in a reduced proliferation and invasiveness, but had no effect on cell viability or apoptosis. Together, these data reveal that sortilin is expressed in aggressive breast cancers and is a potential therapeutic target.

Citation Format: Jay Pundavela, Severine Roselli, Yohann Demont, Sam Faulkner, John Attia, Sheridan Keene, Marjorie M Walker, Hubert Hondermarck. The neuronal protein sortilin is expressed in aggressive breast cancers and participates in tumor cell growth and invasion [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-11.
Abstract P6-02-03: SUMO Inhibitors affect tumorigenesis of novel breast cancer xenograft model
Authors: Bogachek Maria V , Park Jung M , De Andrade James P , Kulak Mikhail V , White Jeffrey R , Wu Tong , Spanheimer Philip M , Woodfield George W , Bair Thomas B , Olivier Alicia K , Weigel Ronald J
Published: May 2015

A novel basal breast cancer cell line IOWA-1T was derived from chemotherapy resistant locally advanced breast cancer tumor. The cells rapidly form large, skin-eroding xenografts in nude mice. The SUMO inhibitor anacardic acid (AA) effectively cleared CD44+/hi/CD24-/low cancer stem cell (CSC) population in IOWA-1T and BT-20 basal cancer cell lines and delayed tumor outgrowth of basal cancer xenografts. The effect of SUMO inhibitors to clear the CSC population was dependent upon the SUMO unconjugated form of TFAP2A (Bogachek MV et al, Cancer Cell, 2014). Herein we show that tumors that eventually form from IOWA-1T xenografts in mice treated with AA are not capable of developing secondary xenografts, confirming eradication of the CSC population by SUMO inhibitors. As further mechanistic evidence for the SUMO pathway, transient knockdown of UBC9 and PIAS1 SUMOylation enzymes repressed CD44 expression and increased tumor free and overall survival in mice inoculated with IOWA-1T xenografts. Furthermore, CD44 downregulation was demonstrated in IOWA-1T cells after treatment in vitro with UBC9 inhibitor PYR-41 and PIAS1 inhibitor NSC-207895. Overall survival of mice with IOWA-1T xenografts was increased to 43±0.5 and 39±2 days with PYR-41 and NSC-207895 i.p. injections, respectively, compared to a vehicle treated control group 33±1 days (p<0.05). By contrast, doxorubicin treatment was not able to extend survival of mice with IOWA-1T xenografts. These findings establish the class of SUMO inhibitors as potential therapeutic drugs that eliminate the breast CSC population and may be effective in basal breast cancer cases resistant to conventional chemotherapy.

Citation Format: Maria V Bogachek, Jung M Park, James P De Andrade, Mikhail V Kulak, Jeffrey R White, Tong Wu, Philip M Spanheimer, George W Woodfield, Thomas B Bair, Alicia K Olivier, Ronald J Weigel. SUMO Inhibitors affect tumorigenesis of novel breast cancer xenograft model [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-02-03.