bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-04-06: Damage-induced BRCA1 phosphorylation contributes to the timing of end resection
Authors: Parameswaran B , Chiang H-C , Lu Y , Hu Y 
Published: August 2014

Abstract
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 functions as a tumor suppressor. A wealth of evidence has established that BRCA1 plays an important role in DNA repair and cell cycle checkpoint control. Efficient repair of double-strand-breaks (DSBs) by BRCA1 is essential to its tumor suppression function. DSBs can be repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ). BRCA1 is hyperphosphorylated upon DSBs. Although phosphorylation of BRCA1 is among the earliest events documented upon DNA damage, the role of BRCA1 phosphorylation in DNA repair remains unclear after more than a decade. It has been proposed that BRCA1 serves as a scaffolding protein that recruits multiple repair proteins to the break sites. One of the BRCA1-containing complexes, MRN (Mre11-Rad50-Nbs1)-BRCA1-CtIP, promotes HR repair by initiating DNA end-resection, the first step in the HR pathway. Mre11 possesses intrinsic nuclease activity, which likely facilitates initial processing of DNA ends for subsequent extensive end-resection. Believed to stimulate the nuclease activity of the MRN complex, CtIP is recruited to the complex by BRCA1.
In spite of these useful molecular models, the precise function of BRCA1 in DSB repair, especially the role of its phosphorylation, remains elusive. BRCA1 is phosphorylated by Chk2 kinase upon g-irradiation at serine 988 (human) or serine 971 (mouse). Our data shows that a point mutation in mouse BRCA1 (S971A) that abolishes the Chk2 phosphorylation site impairs end-resection after DSBs. The S971A mutation does not appear to affect the assembly of MRN and CtIP at DSBs, but specifically delays dispersion of BRCA1 from DSBs. Interestingly, BRCA1 is ubiquitinated and degraded by SCFSkp2, and loss of Chk2 phosphorylation at S988 of human BRCA1 impairs its ubiquitination. Previous work has revealed BRCA1 as a scaffold protein for the assembly of HR proteins at DSBs. Paradoxically, BRCA1 also inhibits Mre11 nuclease activity. Our study suggests that BRCA1 plays a dual role in HR. Although BRCA1 is required for initial assembly of the MRN-BRCA1-CtIP complex at DSBs, the exit of BRCA1 from the MRN-BRCA1-CtIP complex is required to relieve its inhibitory effect on Mre11 nuclease activity. Mechanistically, this critical “exit” of BRCA1 from the MRN-BRCA1-CtIP complex is regulated through phosphorylation catalyzed by Chk2 and then degraded by SCFSkp2, which is expressed at S/G2 phases, thus ensuring the initiation of end resection/HR to S/G2 phases of the cell cycle. Our study explains two seemingly paradoxical observations: BRCA1 is required for assembly of the MRN-BRCA1-CtIP complex, but it inhibits Mre11 nuclease activity required for end-resection.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-04-06.
Abstract P3-05-05: Classification using dynamic re-discovery of the strongest prognostic features in each analysis outperforms static gene expression signatures for prognostic prediction in breast cancer
Authors: Györffy B , Karn T , Sztupinszki Z , Weltz B , Müller V , Pusztai L 
Published: August 2014

Abstract
Introduction: To overcome limitations of previous multigene prognostic classifiers, we propose a new dynamic predictor. Our classifier does not use a single universal training cohort and an identical list of informative genes to predict the prognosis of new cases but a case-specific predictor is developed for each test case.
Methods: We analyzed gene expression data from 3,534 breast cancers with clinical annotation including survival. For each test case we select a case-specific training subset including only molecularly similar cases and a case-specific predictor is generated. This method yields different training sets and different predictors for each new patient but preserves the independence of model building and validation. The model performance was assessed in leave-one-out validation and also in 325 independent cases.
Results: Prognostic discrimination was high for all cases (n = 3,534, HR = 3.68, p = 1.67E-56). The dynamic predictor showed higher overall accuracy (0.68) than genomic surrogates for the 21-gene predictor (0.64), the 97-gene genomic grade index (0.55) or the 70-gene prognostic signature (0.41). The dynamic predictor was also effective in triple-negative cancers (n = 427, HR = 3.08, p = 0.0093) where the above classifiers all failed. Validation in independent patients yielded similar classification power (HR = 3.57).
Discussion: We developed a new method to make personalized prognostic prediction using case-specific training cohorts. The dynamic predictors outperform static models developed from single historical training cohorts and they also predict well in triple-negative cancers. The dynamic classifier is available on line at http://www.recurrenceonline.com/?q = Re_training.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-05.
Abstract P3-05-09: Interlaboratory variability of Ki67 labeling index in breast cancer tissue microarrays
Authors: Focke CM , Gläser D , Finsterbusch K , Bürger H , Korsching E , Berghäuser K-H , Hinrichs B , Krause U , Lorenzen J , Packeisen J , van Diest PJ , Decker T 
Published: August 2014

Abstract
Objective: Assessment of tumor proliferation using the Ki67 labeling index (Ki67-LI) is increasingly recommended for prognostication and adjuvant chemotherapy decisions in breast cancer. Our aim was to investigate interlaboratory variance of Ki67-LI results using TMA and centralised assessment to exclude preanalytic influences and postanalytic variance, respectively.
Methods: Nine pathology laboratories (8 German and 1 Dutch) performed Ki67 staining of a TMA slide according to their routine in house protocol (including internal and external quality assurance). 40 samples per lab were centrally analyzed. The Ki67-LI was calculated after counting first all tumor cells and subsequently all Ki67 positive tumor cells of each sample regardless of staining intensity. For each tissue sample we evaluated the range of Ki67-LIs between different labs. Further 20 labs of the German Breast Screening Pathology Initiative will participate in 2013.
Results: The range of Ki67-LIs between the labs was: 1-5% in 4 (10%), 6-10% in 6 (15%), 11-15% in 7 (17,5%), 16-20% in 2 (5%), 21-25% in 7 (17%), 26-30% in 4 (10%), 31-35% in 1 (1%), 36-40% in 4 (10%), 41-45% in 2 (5%), 46-50 in 0 (0%) and &gt;50% in 3 samples (7%), respectively. Thus, in 35% of results of the 9 labs (26 of the 40 TMA specimens) the Ki67-LI differed by more than 25%. The analysis of variance (ANOVA) came out with F = 4.24 which is much larger than the critical F value of 1.97 for these study results (p = 7.74902E-05). This means that the observed interlaboratory variance of 4.24 is systematic and not due to sampling error. The respective standard deviation is 33.4%.
Conclusion: In a setting strictly standardised in terms of preanalytic influences by using TMA and postanalytic variance by centralised quantification, Ki67-LI seems to be heavily influenced by laboratory-specific analytic variables. Taking this into consideration, there may be a risk of prognostic or predictive misclassification in some breast cancer patients in daily practice.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-09.
Abstract P3-06-05: HER2/HR positive early breast cancer patients have nowadays the highest disease-free survival: Results from the south-east of the Netherlands
Authors: Tjan-Heijnen VCG , Lobbezoo DJA , Dercksen M , Voogd AC , van den Berkmortel F , van de Wouw AJ , van Kampen RJW , Peer PGM 
Published: August 2014

Abstract
Background
Adjuvant systemic therapy choices in early breast cancer largely depend on human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status. Overexpression of HER2 has been shown to be associated with a worse outcome (Slamon et al, Science, 1987). With this cohort study, we aimed to assess the outcome of early breast cancer patients per subtype based on HER2 and HR status in daily practice treated in a time period of routine use of anti-HER2 treatment.
Patients and methods
Patients diagnosed with early breast cancer during the years 2005-2007 in five participating hospitals in the South-East part of the Netherlands were included. Patients with primary metastatic breast cancer were excluded. Information regarding disease characteristics and treatment was collected. Patients were categorized in 4 subtypes based on the HER2 and HR status of the primary tumor: HER2 positive (+)/HR positive (+), HER2 negative (-)/HR+, HER2+/HR-, and triple negative (TN) (i.e. HER2- and HR-). Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders.
Results
A total of 2579 patients were included with a median follow-up of 52.6 months.
Median 5-year DFS rate was highest for the HER2+/HR+ subtype (comprising of 13% of all patients) with 78%, compared to 68% for the HER2+/HR- subtype (5% of all patients), 75% for the HER2-/HR+ subtype (70% of all patients) and 64% for the TN subtype (12% of all patients).
In multivariate analysis, subtype was confirmed to be an independent prognostic factor. Compared to the HER2+/HR+ subtype, the HER2+/HR- subtype was associated with a worse DFS (HR 2.05, 95% CI 1.21-3.46, P = 0.008) and the HER2-/HR+ was associated with a similar DFS (HR 1.09, 95% CI 0.79-1.52, P = 0.6). Furthermore, classical clinicopathological parameters were all confirmed to be of independent prognostic relevance, as well as the use of adjuvant systemic therapy. At the meeting, we will show the results according to the type of adjuvant systemic treatment used.
Conclusion
In this cohort, we noted that 13% of patients had HER2+/HR+ early breast cancer. These had the highest 5-year disease-free survival of all subtypes, significantly better than the HER2+/HR- subgroup. This may indicate a differential prognostic impact of HER2 according to HR status, with HR+ having a positive prognostic impact, irrespective of the presence of HER2 overexpression.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-05.
Abstract P3-06-14: Increase in the proportion of stage IV breast cancer amongst young women with newly diagnosed breast cancer, report from the National cancer data base, 1998-2009
Authors: Yao K , Tomasz C , Pesce C , Huo D , David WJ , David WP , Edward W 
Published: August 2014

Abstract
Background: A recent SEER study showed a significant increase in the incidence of advanced breast cancer in women 25 to 39 years old. We hypothesized a similar trend amongst newly diagnosed breast cancer patients treated at Commission on Cancer Accredited Cancer Centers in the United States and that such increase is greatest among minority young women.
Methods: We utilized data from the National Cancer Data Base to determine the proportion of patients &lt;40 years old who were diagnosed with Stage IV disease from 1998-2009. Patient demographics (insurance, race, income) and tumor characteristics (size, node status, grade, estrogen receptor (ER), histology) were included to compare the risk factors associated with advanced disease between younger and older women. Statistical analyses were performed using both univariate and multivariable logistic regressions in SAS 9.3 (SAS Inc., Cary, NC).
Results: A total of 1,955,190 women with newly diagnosed breast cancer were included. The proportion of young women (&lt;40 years old) diagnosed with stage IV breast cancer has increased by 58% between 1998 and 2009 (Table 1). This increase in young women was significantly greater than other age groups with Stage IV disease: 40-54 years old (Δ = 9%), 55-69 (Δ = 13%) and &gt;70 years old (Δ = 17%) (all p&lt;0.001). Amongst women with stage IV disease, women &lt;40 years old compared to women ≥40 years old were more likely to be nonwhite (29% vs. 19%, p&lt;.0001), have grade III tumors (70% vs. 57%, p&lt;.0001), have an estrogen receptor (ER) negative tumor (34% vs. 28%, p&lt;.0001), and have a ductal carcinoma (85% vs. 78%, p&lt;.0001). In the multivariable analysis, young women (&lt;40 yr) remained at significantly greater risk of being diagnosed with stage IV disease (OR = 1.19, 95% CI 1.14-1.24, p&lt;.0001) compared to women ≥40 years old after adjusting for income, race/ethnicity and tumor characteristics. While the proportion of women with stage IV disease has increased between 1998 and 2009, the increasing odds was significantly greater among young women (OR = 1.54) as compared to old women (OR = 1.17) in the risk adjusted multivariable models.
Table 1. Trend in proportion of women diagnosed with Stage IV disease according to patient age, 1998 and 2009.Age19982009Age &lt;401.973.12Age 40-541.471.61Age 55-691.591.81Age 70+1.802.11
Conclusions: The proportion of women with stage IV disease under 40 years old has increased significantly over the past decade and this trend was not seen in older age groups. Young minority women with ER negative tumors are at greatest risk to be diagnosed at a later stage.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-14.
Abstract P3-06-16: The difference of molecular subtypes and prognosis after surgery for breast cancer patients with each blood types
Authors: Kondo N , Fujita T , Sawaki M , Hattori M , Horio A , GONDO N , Idota A , Ichikawa M , Iwata H 
Published: August 2014

Abstract
(Introduction) ABO blood type has been associated with various malignancies, including pancreatic and stomach cancer. However the correlation between blood type and hormone receptor (ER/PR), HER2/neu, patient outcomes remains largely unexplored in patients with breast cancer.
(Methods)This study involved retrospective chart review of patients diagnosed with primary breast cancer stages I-III at Aichi Cancer Hospital between January 2004 and December 2011. Among 1944 breast cancer patients, the relationships between ABO blood type and clinicopathological findings, outcomes were analyzed. Descriptive statistics and c2 analysis were utilized for data summary and comparisons.
(Results) Of 1944 patients, 723 (37%), 577 (29%), 446 (23%), 198 (11%) were blood type A, O, B, AB respectively. This distribution is similar to that reported previously for general Japanese population. 327 (16.8%) patients were ductal carcinoma in situ and 1617 (83.2%) were invasive cancer, and there were no significant differences in this distribution based on each blood types. Among 1617 invasive breast cancer patients, we did not observe significant associations between blood type and pathological T stage or pathological N stage. However, patients with blood type O had lower rate of Luminal type (68.2%) compared blood type A, B, AB (73.5%, 75.2% and 76.0%, respectively (P = 0.03). The blood type O had higher rate of Tripe Negative type (13.7%) compared blood type A, B, AB (10.6%, 9.9% and 8.4%, respectively (P = 0.04). No other statistically significant differences in baseline characteristics among the four blood type groups were noted. No significant differences were observed in type of treatment (endcrine therapy, chemotherapy and anti-HER2 therapy) in each breast cancer subtypes among four blood type groups. Compared to women with blood type A, there was no significant difference in disease free survival among the for blood type O [hazard ratio (HR) 1.754; 95% confidence interval (CI) 0.735-2.731], blood type B (HR 0.978; 95% CI 0.724-1.542.), blood type AB (HR 1.235; 95% CI 0.694-2.864). For patients with blood type O, this difference did not reach statistical significance, although a trend toward worse prognosis of the patients with blood type O status was seen.
(Conclusion) The blood type O had lower rate of Luminal type and higher rate of Tripe Negative type compared other blood types. No significant differences were observed in disease-free survival according to ABO blood types.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-16.
Abstract P3-07-06: BRCA mutations among Hispanic breast cancer patients of Mexican origin in El Paso, TX
Authors: Nahleh ZA , Heydarian R , Saldivar JS , Castaneda K , Sanchez L 
Published: August 2014

Abstract
Introduction: El Paso, TX is a large American-Mexican border city of population around 900,000, 85% Hispanic of Mexican origin. Limited cancer research has been conducted in this population. The relative homogeneity of this Hispanic population lends a unique opportunity to study the prevalence of BRCA mutations among Hispanic patients of Mexican origin, to identify reported Mexican founder or recurrent mutations, and to study the breast cancer characteristics in mutation carriers. Methods: Hispanic women with a personal history of breast cancer, who presented consecutively for genetic cancer risk assessment, were enrolled in an Institutional Review Board -approved registry and underwent BRCA testing bases on NCCN guidelines. The characteristics of tumors and patients with positive BRCA mutation were analyzed. Descriptive statistics were utilized. Results: 59 patients were screened; 13 patients (22%) tested positive. Mean age was 50 years; 8 patients (62%) had stages I or II, 2 patients stage III, and 3 unknown. 10 (77%) ductal, 1 (7%) lobular and 2 undetermined; 30% had ER positive tumors versus 61% ER negative; 69% had HER2 -neu negative tumors and 23% HER2-neu positive; 62% were triple negative. Nine patients (69%) were diagnosed with breast cancer at younger than 50 years. Median BMI was 31.78. Ten patients had BRCA1 mutations and 3 BRCA2 mutations. A total of 9 unique deleterious BRCA Mutations were observed, BRCA1 R71G (330A&gt;G);del exons 1-2;C1787S(5478T&gt;A) and G1788D(5482 G&gt;A); C1225X (3794 C&gt;A); A 1708E(5242 C&gt;A); R1751X(5370C&gt;T; and del exons 9-12 and BRCA2 Q742X (2452 C&gt;T); and 3492 insT Conclusion: This study confirms that breast cancer patients with BRCA mutations in the El Paso, TX present at a younger age, and have predominantly triple negative tumors. Of particular interest is 44% (4 of 9) BRCA mutations (BRCA1 exon 9-12 del; C1787S & G1788D and BRCA 2 3492insT; Q742X) identified have been reported as recurrent mutations in Hispanic individuals from Mexico as the country of origin, including BRCA1 ex9-12del, the 1st Mexican founder mutation and 100% of the BRCA2 mutations. A more cost-effective approach to initial screening of Hispanic individuals based on country of origin may be desirable and would potentially decrease the number of cases requiring complete sequencing. Increasing breast cancer awareness and encouraging genetic counseling among high risk younger patients of Mexican descent is also needed.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-06.
Abstract P3-07-10: Breast cancer risk-related gene polymorphisms, ESR1/6q25.1-rs2046210 and rs3757318, and clinical characteristics of breast cancer patients
Authors: Taira N , Mizoo T , Nishiyama K , Nogami T , Iwamoto T , Motoki T , Shien T , Matsuoka J , Doihara H , Ishihara S , Kawai H , Kawasaki K , Ogasawara Y , Ishibe Y 
Published: August 2014

Abstract
[Background] Based on the results of a case-control study performed in Japan (Okayama and Kagawa), it was revealed that gene polymorphisms of the estrogen receptor (single nucleotide polymorphisms, SNPs), ESR1/6q25.1-rs2046210 and SNPs of rs3757318 were closely related to breast cancer risk in Japanese women, and that the odds ratio per allele of individual SNPs were 1.37 [95% CI: 1.1 - 1.7] and 1.33 [1.04 - 1.7], respectively (San Antonio Breast Cancer Symposium 2012, Mizoo et al.). We analyzed the relationship of ESR1/6q25.1-rs2046210 and rs3757318 SNPs with the clinical characteristics of breast cancer patients.
[Methods] Among the patients enrolled in the case-control study, 508 breast cancer patients who underwent genotyping for ESR1/6q25.1-rs2046210 and rs3757318 were analyzed as the subjects. SNPs were analyzed using the TaqMan genotyping assay® for blood samples. To analyze the relationship of genotypes (AA/GG, GG) with age at diagnosis, height, weight, BMI, age of menarche, birth history, pathological degree of progression and estrogen receptor, t-test and chi-square test were used.
[Results] The genotypes of rs2046210 are AA (12%), AG (41%) and GG (46%), and the patients with the risk allele (AA/AG) had significantly higher height (p = 0.0015, t-test) and lower Body Mass Index (BMI) (p = 0.0022, t-test). The genotypes of rs3757318 are AA (8%), AG (39%) and GG (53%), and the patients with the risk allele (AA/AG) were characterized by significantly lower BMI (p = 0.041, t-test), no birth history (p = 0.0473, chi-square) and negative hormone receptor (p = 0.0128, chi-square). Overall, tendencies related to increased height, lower BMI and negative estrogen receptor were confirmed for the risk alleles of rs2046210 and rs3757318.
[Conclusion] It was suggested that SNPs of rs2046210 and rs3757318 might be related to the development of estrogen-receptor-negative breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-10.