bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Genomic Biomarker for Breast Cancer Development in High-Risk Women.
Authors: Bild A. , Sun Y. , Soldi R. , Conner T. , Walker D. , Werner T. , Spira A. , Andrulis I. , Buys S. , Johnson E. 
Published: December 2010

Abstract
BackgroundFamily history is an important factor contributing to a woman's risk of breast cancer development. This increased risk reflects the participation of inherited genetic components such as breast cancer susceptibility genes. However, many of the genetic components contributing to breast cancer remain unknown, and a number of women with a family history of breast cancer never develop breast cancer despite their high-risk status, while other high-risk woman go on to develop breast cancer. Thus, it is clear that we lack crucial pieces of information to help define a person's true risk of developing breast cancer.Methods and FindingsWe hypothesize that there are many undiscovered germline variations in genes that lead to altered gene expression patterns predictive of breast cancer development in high-risk women. We have developed a genomic model capable of predicting which high-risk women, both BRCA1/2 mutation carriers and BRCAX women, will actually develop breast cancer. Specifically, we use exon-level genome-wide expression profiling of peripheral blood mononuclear cells (PBMCs) to develop a model of disease risk (n=118 samples of either control or high-risk women). From this data, we generate a biomarker consisting of genes that most correlate to cancer development in women with strong family histories of breast cancer. Using an internal independent dataset, our biomarker can predict the high-risk women who will or will not develop cancer with over 85% accuracy. Further, we have validated this model on an independent external cohort (n=36) which was obtained and processed at sites unique to our training dataset. Our genomic biomarker can accurately predict breast cancer development in high-risk women with over 78% accuracy using this external dataset. Therefore, from our analyses, we can calculate with high accuracy an individual woman's true risk of developing breast cancer. This method provides a personalized approach to hereditary breast cancer risk assessment that is not currently available. This personalized risk assessment will aide clinicians in counseling their patients regarding specific management options based on a patient's individual risk of breast cancer. Lastly, these studies have also identified novel genes associated with breast cancer risk, which may provide a basis for targeted therapies that may help modify the risk of breast cancer development in high risk patients.ConclusionsTogether, these studies deliver both a non-invasive biomarker for hereditary breast cancer risk and a characterization of genes that contribute to breast cancer development. Overall, we expect these experiments to identify the genetic changes that underlie breast cancer predisposition, and assist clinicians and patients in determining the appropriate preventative measures based on their personal risk of developing breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4059.
Ki-67 Expression after Tamoxifen Given Preoperatively Predicts Disease Free Survival and Overall Survival in Women with Operable ER-Positive Breast Cancer.
Authors: Decensi A. , Decensi A. , Guerrieri-Gonzaga A. , Gandini S. , Serrano D. , Cazzaniga M. , Mora S. , Johansson H. , Lien E. , Lien E. , Luini A. , Pelosi G. , Pelosi G. , Bonanni B. 
Published: December 2010

Abstract
We have previously shown in a window of opportunity, 3-arm, double-blind phase II randomized trial conducted in a single Institution that tamoxifen given for 4 weeks between tru-cut biopsy and surgery at a daily dose of 5 or 1 mg day was equivalent to 20 mg in decreasing ki-67 expression. A total of 31 premenopausal and 89 postmenopausal women with operable stage I-II ER-positive breast cancer were recruited (Decensi A et al, JNCI 2003;95:779-90). Here we analyzed the prognostic and predictive significance of ki-67% after a median follow-up of 86 months (11-111) in the same cohort of 120 women who underwent adjuvant treatment according to St. Gallen guidelines. At the current follow-up time DFS was 76% and OS was 92%. The median (IQ range) post-treatment ki-67% value was 12% (7-17) in women free of recurrence versus 20% (11-29) in women who relapsed (p=.0014). Post-treatment (surgery) ki-67% was positively associated with worse prognosis in univariate analysis (log-rank test =.0009, with ki-67% categorized in three groups: &lt;7 (n=24), 7-19 (n=63), ≥20 (n=29); Figure).Post-treatment ki-67% was significantly associated with breast cancer death as well (p=.005, ki-67% &lt;20 versus ≥20). In multivariate Cox analysis of DFS, both pre- and post-treatment ki-67 used as continuous variables were significantly associated with a higher risk of recurrence independent of adjuvant treatment, estrogen receptor level and pre-surgical tamoxifen dose (p=.002 and .04, respectively). Women with post-treatment ki-67% in the middle tertile (7-19%) and top tertile (≥20%) had a HR=2.1 (0.5-9.7) and HR=6.7 (1.5-30.2) of recurrence compared with women in the bottom tertile, respectively. There was no significant difference among tamoxifen dose groups on recurrence or death. In multivariate Cox analysis of OS, both pre- and post-treatment ki-67 used as continuous variables were significantly associated with a higher risk of breast cancer death (p=.0453 and .003, respectively). The risk of breast cancer death was 5 times higher in women with post-treatment ki-67 &gt;20% than in women with ki-67&lt;20% (HR=5.26, 1.22-23, p=.03). Our findings indicate that ki-67 is a prognostic and predictive marker in women with operable ER-positive breast cancer. The modulation of Ki-67% after a few weeks of hormonal intervention before surgery is a promising surrogate biomarker for outcome prediction and provides the opportunity to screen active agents in a cost-effective manner.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 406.
Screening for BRCA1 Mutations in Patients with Triple Negative Breast Cancer and Basal Phenotype.
Authors: Somer R. , Farengo-Clark D. , Patel A. , Schwarting R. , Grana G. , Rodler E. 
Published: December 2010

Abstract
Introduction: Most models estimating risk of carrying germline BRCA mutations are based on family history and age of cancer onset. Additional histologic criteria may be useful to identify patients at risk for harboring BRCA1 mutations. BRCA1 positive breast tumors are significantly more often estrogen receptor, progesterone receptor, and erbB-2 (HER2-neu) negative (“triple negative” (TN)) and are strongly associated with a basal phenotype confirmed by DNA microarray. Basal-like tumors express cytokeratins 5,6, and 14 or 17 by immunohistochemistry (IHC). It is unknown whether testing for BRCA1 mutations in TN basal-like breast cancer patients will identify additional carriers of mutations in this gene.Methods: A retrospective evaluation of patients with triple negative breast cancer seen at Cooper Cancer Center between 2004 and 2006 was performed after IRB approval. IHC was performed to identify the subset of basal-like breast cancers.Results: A total of 89 women were identified as diagnosed with TN breast cancer, while 53 had pathology available for review. 21 patients were identified as basal phenotype, whereas 32 were non-basal. Of the 21 patients who had basal-phenotype tumors, six underwent genetic testing and 3 were found to have a deleterious BRCA1 mutation. Of 32 non-basal patients, 9 patients underwent genetic testing and 2 were found to have a deleterious BRCA1 mutation. There was no difference between basal subtype and BRCA1 postivity [Fisher's Exact Test p=0.32]. Of note, 1of 5 (20%) patients with basal phenotype had no family history but tested positive for BRCA1 mutation and would have been missed by relying on conventional methods.Conclusion: Although there is a trend towards a higher percentage of TN breast cancer patients with basal subtype having BRCA 1 mutations (50 vs 22%), this was not found to be statistically significant (Fisher's exact p=0.32). However, this dataset is limited by a small sample size. Only 40% of TN breast cancer patients had a basal phenotype by IHC in this study, while other studies have shown 70- to 85% rate. Ongoing evaluation of patients with basal-like subtype and triple negative tumors should continue to investigate this relationship, especially in light of newer therapeutics that may impact this population. This data also suggests that patients with basal phenotype and triple negative disease should be considered for referral for genetic testing even in the absence of family history.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4075.
A Phase II Study of the Combination of Endocrine Treatment and Bortezomib in Patients with Endocrine Resistant Metastatic Breast Cancer.
Authors: Trinh X. , Van Laere S. , Deleu I. , van de Velde H. , Van der Auwera I. , Limame R. , Wojtasik A. , Maes H. , De Mesmaeker P. , van Dam P. , Prové A. , Vandebroek J. , Rasschaert M. , Vermeulen P. , Dirix L. 
Published: December 2010

Abstract
Background: The introduction of anti-hormonal treatment has been a major revolution in breast cancer management. The majority of patients with metastatic hormone receptor-positive breast cancer eventually suffer from progression of their disease despite different types of anti-hormonal treatment. Preclinical studies have indicated bidirectional inhibitory interactions between ER and NF-kappaB, governing in part endocrine-resistance and enhanced growth. The hypothesis that inhibition of NF-kappaB activation by a proteasome inhibitor might reverse the sensitivity to endocrine therapy was the rationale to initiate a phase II trial.Aim, Material and Methods: The aim is to investigate whether the addition of open label bortezomib to either a SERM or an AI will result in documented activity in patients with progressive and measurable disease on the identical endocrine agent. This endpoint is evaluated according to RECIST criteria every 8 weeks. The patients are stratified into 2 treatment groups, according to their current endocrine treatment either tamoxifen or an AI. Bortezomib is administered on days 1, 8, 15, 21 of a 6 week regimen at a dose of 1.6 mg/sqm on each treatment day. Consecutive tumour biopsies (if accessible) and blood samples are collected for translational purposes. Clinical benefit was predefined by the patients obtaining at least either stable disease, or a partial or a complete response according to RECIST criteria, lasting for at least four weeks. A two-stage statistical approach showed that this should at least occur in 1 patient in the first cohort of 14 patients, prior to further accrual.Results: At present N=9 patients have been enrolled. Eight patients received AI+bortezomib, while one received TAM+bortezomib. N=5/9 patients had progressive disease, N=4/9 patients had stable disease of which two patients (N=2/9) had stable disease continuing for more than 4 weeks. There were no objective antitumour responses observed. N=4/9 had grade III diarrhoea. Median time to treatment failure was 69 days [35-140], either due to toxicity (N=3/9) or (eventual) progression (N=6/9).Conclusions: Preliminary results shows that the clinical benefit rate is 22% (N=2/9). Although preliminary, these results warrant further accrual and suggest that the biological hypothesis seems clinically valid. Further recruitment is ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4099.
Final Overall Survival (OS) Results from the Randomised, Double-Blind, Placebo-Controlled, Phase III AVADO Study of Bevacizumab (BV) Plus Docetaxel (D) Compared with Placebo (PL) Plus D for the First-Line Treatment of Locally Recurrent (LR) or Metastatic Breast Cancer (mBC).
Authors: Miles D. , Chan A. , Romieu G. , Dirix L. , Cortés J. , Pivot X. , Tomczak P. , Juozaityte E. , Harbeck N. , Steger G. 
Published: December 2010

Abstract
Background: Anti-VEGF monoclonal antibody BV significantly improves efficacy in combination with standard therapies in multiple tumour types, with limited impact on toxicity. Three randomised phase III trials (E2100, AVADO and RIBBON-1) in mBC have demonstrated that BV + 1st-line chemotherapy (CTx) significantly improves progression-free survival (PFS) and overall response rates (ORR). We present mature OS data from AVADO.Methods: Patients (pts) with HER2-negative LR/mBC were randomised to D 100mg/m2 + PL, D + BV 7.5mg/kg or D + BV 15mg/kg. D was given q3w for ≤9 cycles. BV or PL was given q3w until disease progression/unacceptable toxicity. After progression, pts were offered BV with 2nd-line anticancer therapy in a post-study treatment phase. The primary endpoint was PFS; secondary endpoints included OS, time to treatment failure, ORR, duration of response and safety. An exploratory analysis conducted in pts receiving post-progression CTx compared OS in pts receiving 2nd-line BV with those who did not.Results: 736 pts were enrolled March 2006–April 2007. The primary analysis (data cut-off October 2007; median follow-up 10.2 months) showed significant improvements in PFS and ORR for both BV-containing arms compared with PL + D. Mature OS data (data cut-off April 2009; median follow-up 25 months) are shown (Table). There was no difference in median OS between the study arms (range 30–32 months). Recognising the limitations of the non-randomised comparison in exploratory analyses, results suggest that use of BV with 2nd-line therapy is a possible reason for lack of OS difference. Updated PFS and ORR were superior for the 15mg/kg BV arm compared with PL + D. Results for the 7.5mg/kg BV arm also indicated a, less pronounced, treatment benefit. BV had limited impact on the safety profile of docetaxel. Increased SAEs in the 15mg/kg BV arm may be due to more pts receiving 9 cycles of D than in the PL arm (51% vs 42%).Conclusions: There was no difference in OS between study arms. Exploratory analyses suggest that use of 2nd-line BV with CTx may influence OS. These mature data confirm the improvement in PFS and ORR with BV 15mg/kg combined with D compared with PL + D.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 41.
Does 3D-Ultrasound Imaging Improve Target Delineation for Breast Boost Radiation Therapy Planning.
Authors: Young A. , Chadha M. , Geraghty C. , Harrison L. 
Published: December 2010

Abstract
Background: Conformal volume-based breast dosimetry using CT-simulation is the most widely used technique for treatment planning. As part of a prospective protocol we studied the role of 3D-Ultrasound (US) technique for Image-Guided Radiation Therapy in breast cancer. In this paper we explore if there is additional value to utilizing seroma images on 3D-US for defining the target volume for breast boost.Materials and Methods: The IRB-approved prospective study used the ClarityTM 3D-US breast system (Resonant Medical). At simulation, concurrent CT and 3D-US images were obtained then fused. The boost lumpectomy volume (GTV) was contoured on CT by a single physician blinded to the results of the US (MC). To create the planning target volume (PTV), the GTV was expanded circumferentially by 1.5 to 2.0 cm, with the exception of its relation to skin and chest wall which were excluded from the PTV. For this analysis, the fused images of the concurrent CT simulation and 3D-US obtained on 25 patients were evaluated for concordance in the coverage of the CT contoured GTV and PTV to that of the 3D-US seroma image.Results: In 1 patient the CT images were limited in identifying the lumpectomy cavity because of the dense nature of the breast. The cavity not appreciated on CT image was visible on US. In this case the application of 3D-US would have provided superior target definition. In 22 of the remaining 24 patients the seroma cavity seen on the US was also seen on CT and was included in the lumpectomy GTV contoured on the images from CT simulation. In 2 patients, approximately 5% of the US seroma was not part of the GTV but was encompassed in the expanded PTV. In these 2 patients the US seroma was in proximity to the edge. This eccentric location of the US seroma cavity in 1 out of the 2 patients would have resulted in a change in the PTV. While in the other patient even though the seroma cavity was close to the edge of the PTV, the proximity to the chest wall would have precluded any major modification of the PTV. Overall, in all cases the 3D-US seroma cavity was encompassed in the expanded PTV. In 2/25 patients the target volume would have been revised based on the additional data provided by the 3D-US images.Conclusions: In summary, from this experience we observed that the use of 3D-US images in addition to CT simulation can alter the target delineation in 8% of cases. The 3D-US is a non-ionizing imaging modality that may add benefit for improving target delineation when used concurrently with CT simulation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4107.
Examination of Immune Competence in Breast Cancer Patients at Six Months Post Surgery and Adjuvant Therapy through Assessment of T Cell and Dendritic Cell Functionality.
Authors: Gendler S. , Pathangey L. , Lakshminarayanan V. , Mukherjee P. , Pockaj B. , Suman V. , Loserth L. , Markovic S. , Ingle J. 
Published: December 2010

Abstract
It has long been known that immune suppression is induced by the presence of a tumor, resulting in compromised T cell and dendritic cell (DC) functionality. What is not well understood is how soon the immune system recovers normal functionality following surgical removal of tumors and adjuvant therapy. This timing is of critical importance, as the effectiveness of therapeutic immune strategies relies on optimal presentation of antigens and activation of T cells. Blood from breast cancer patients was collected prior to surgery and at 3 and 6 months post adjuvant therapy. Patients were treated with surgery (breast conservation or mastectomy) and chemotherapy (CT) (n=22) or surgery without chemotherapy (n=38). Most patients had radiation therapy (RT). Blood from 22 healthy woman of similar age served as controls. T cell functionality (TCF) was determined following stimulation with plate-bound anti-CD3 (1 µg/ml) and anti-CD28 (0.5 µg/ml) and proliferation was measured by 3H-thymidine uptake. DC functionality (DCF) was determined by ability to present allo-antigens in a mixed lymphocyte reaction. Values for the normal samples determined the normal ranges (NR). Responses were grouped into 4 categories based on their status at 6 months: Group 1 - remained in NR; Group 2 - climbed into NR; Group 3 - remained below NR; Group 4 - fell below NR. Analysis of immunosuppression will be based on lymphocyte subsets, cytokine, COX-2, and PGE2 metabolite levels.T Cell Proliferation AllWith CTNo CT N=60N=22N=38Group 120%14%24%Group 223%23%24%Group 338%41%37%Group 418%23%16% DC Function AllWith CTNo CT N=58N=20N=38Group 143%35%47%Group 219%25%16%Group 317%15%18%Group 421%25%18% Forty-three percent of patients had normal levels (Groups 1 and 2) for TCF and 62% for DCF by 6 months post adjuvant therapy, suggesting that breast cancer patients are potentially amenable to vaccine therapy. 28% of patients had both TCF and DCF in NR; 50% had either TCF or DCF in NR; and 22% had neither in NR. The percentage of patients who had TCF in NR by adjuvant therapy was: 35% CT+RT (6/17); 33% CT (1/3); 52% (17/33) RT; and 20% (1/5) neither. The percentage of patients who had DCF in NR by adjuvant therapy was: 67% (10/15) CT+RT; 33% (1/3) CT; 67% (22/33) RT; and 40% (2/5) neither. Proper understanding of the effects of tumor, chemotherapy and radiation therapy on immune function, especially the effects on T cells and DCs, may enable us to identify the appropriate patients in whom to study immunotherapy approaches in women with early breast cancer and to examine strategies to counteract cancer-related defects in immune function. (supported by P50CA116201)
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4131.
Peri-Operative Suppression of Immune-Regulatory Blood Cells Predicts Wound Complications in Breast Cancer Patients.
Authors: Hogan B. , Peter M. , Thorpe R. , Achuthan R. , Carter C. , Horgan K. , Hughes T. 
Published: December 2010

Abstract
IntroductionWe have previously demonstrated an association between post-operative wound complications and systemic breast cancer recurrence (p&lt;0.0001), Murthy et al (2007) Br J Cancer 97, 1211-7. The aim of this study was to examine the potential role of the immune system in establishing this association, and therefore whether immune factors might be used to predict either wound complications or cancer recurrences.MethodsPatients with primary operable breast cancer were prospectively recruited to the study. Serial blood investigations were performed pre-operatively, peri-operatively and post-operatively. Absolute numbers of various lymphocyte cell populations were measured using multi-colour flow-cytometry including CD45+lymphocytes, CD19+ B lymphocytes, CD3+ T lymphocytes, CD4+ helper T cells, CD8+ cytotoxic T cells and CD56+ NK cells. We also measured the levels of the NK cytotoxicity receptors NKp30 and NKp46 on the NK cell population.ResultsOne hundred and nine patients were recruited to the study and there was a wound complication rate of 13.4%. Absolute numbers of CD3+ T lymphocytes, CD4+ helper T cells, CD8+ cytotoxic T cells and CD56+ NK cells were significantly lower 4 hours post-operatively compared to pre-operative levels (p&lt;0.05), although levels had typically recovered after 24 hours. However, NKp30 expression remained significantly reduced at 24 hours (p&lt;0.05). Mastectomy patients had a significantly greater fall in T lymphocyte numbers than those having breast conserving surgery (p&lt;0.05). Patients who went on to develop wound complications post-operatively had a significantly greater fall in their CD4+ helper T cells at 4 hours post-operatively, than those patients who did not go on to develop wound complications (p&lt;0.05).ConclusionsBreast cancer surgery results in severe disruption to the immune system, with dramatic changes in levels of immune regulatory blood cells populations. Changes are predominantly immuno-suppressive. The greater the immune disruption as a result of surgery, the more likely the patient is to develop a wound complication. We believe that this peri-operative immuno-suppression may also provide a window of opportunity for the successful dissemination of tumour cells post-operatively thereby increasing the risk of future metastases; we are maintaining follow up on this patient cohort in order to test correlations between peri-operative immuno-suppression and systemic recurrences.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4132.