bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4-07-01: Circulating Tumor Cells, Disease Recurrence and Survival in Newly Diagnosed Breast Cancer.
Authors: Franken B , de Groot MR , Terstappen LWMM , Mastboom WJB , Van der Palen J , Tibbe AGJ 
Published: June 2012

Abstract
Background: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and overall survival (OS) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence free survival (RFS) and breast cancer related death.
Materials and Methods: In a prospective single center study, CTC were enumerated with the CellSearch system in 4 aliquots of 7.5 ml of peripheral blood of 504 patients before undergoing surgery for breast cancer between September 2003 and January 2009. Four hundred four had stage I-III disease and were followed for 6–90 months (median 48). One hundred had a benign tumor and served as a control group. Results: In the control group 15 (15%) had ≥1 CTC / 30 mL of blood. In stage I-III patients 76 (19%) had ≥1 CTC in 30 mL of blood of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (p =0.038). Breast cancer related death was 4,3% (14 of 328 patients) for favorable and 14,5% (11 of 76 patients) for unfavorable CTC (p = 0.001). CTC, PR receptor and stage were independent predictors of breast cancer related death in multivariate analysis. The corrected odds ratio after multivariate analysis for breast cancer related death in patiënts with CTC versus patiënts without CTC was 3,47.
Discussion: Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for recurrence and breast cancer related death. This supports the notion that the presence of CTC is also important in the primary disease setting. In this study the sensitivity of the CellSearch assay was increased by a fourfold increase in blood volume and a threshold for unfavorable of ≥1 CTC in 30 mL of blood, which lead to a relatively high background in the control group. Thus an increase in specificity is desired before initiation of prospective multicenter trials as well as a more practical way to process larger blood volumes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-01.
P4-07-09: Automated Quantitative Assessment of HER2 Expression of Circulating Tumor Cells (CTC) in Metastatic Breast Cancer (IC 2006–04 Study).
Authors: Bidard F-C , Ligthart ST , Decraene C , Bachelot T , Delaloge S , Brain E , Campone M , Pierga J-Y , Terstappen LWMM 
Published: June 2012

Abstract
Background
Beyond quantitative CTC analysis for outcome assessment, their qualitative analysis could predict drug response and resistance. Classification of CTC and quantification of treatment targets on CTC can be subjective as they are morphologically heterogeneous. Current HER2 fluorescence assessment methods rely on a visual comparison between CTC images and external controls (cells lines) and are poorly reproducible. We report an automated classification and quantification of HER2 expression on CTC in a large cohort of metastatic breast cancer (MBC) patients (pts).
Materials and Methods: CTC enumeration and HER2 assessment was performed with the CellSearch® system in pts with MBC included in the prospective IC 2006–04 study (Pierga, Ann Oncol 2011), before first line chemotherapy. The FITC conjugated antibody CB11 was used to identify HER2. For quantitative assessment of HER2 the breast cancer lines SKBR3 and MCF7 with known HER2 status were spiked in blood of normal donors and processed with the CellSearch system. Digital images of Cytokeratin-PE, DAPI, CD45-APC, and HER2−FITC from these samples were stored. An algorithm, previously developed in prostate cancer (Ligthart, AACR 2011), was applied on these images to automate identification of CTC. The fluorescence of the HER2 FITC channel for each CTC as well as the CD45+, DAPI+ leukocytes contained within each sample were also quantified using this algorithm. HER2 fluorescence levels of CTC were compared to HER2 status of status of pts.
Results: Among 267 pts included in this study, 103 had at least 1 CTC/7.5 ml and HER2 fluorescence assessment. In these pts, correlation analysis between automated (aCTC) and manual (mCTC) CTC counts showed an excellent correlation (R2 =0.978). HER2 fluorescence of CTC, varied greatly within and between pts, whereas leukocyte fluorescence was more homogeneous. The vast majority of CTC exhibited less fluorescence than SKBR3 cells, even in HER2+ pts. Primary tumor was HER2+ and HER2− in 36 and 58 pts respectively. Percentage of HER2+ CTC was higher in pts with primary HER2+ status.

Although a rare event, the presence within a sample of at least 1 CTC whose HER2 expression is superior to SKBR3 cells was also strongly associated with HER2+ primary tumor (N=15/36 vs. 3/58; p&lt;0.001).
Conclusion: This study is the first to assess HER2 staining intensity in each CTC isolated from a large number of MBC pts. This was made possible by the aCTC count that was highly correlated with the mCTC count in our cohort and permitted HER2 quantification. Our study shows that HER2 staining is highly heterogeneous among CTC within each pt. These findings demonstrate the feasibility of real time quantitative assessment of treatment targets on CTC and opens a path towards personalized treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-09.
P4-09-03: Clinical Significance of HER2+ and Triple-Negative Status in Patients with Tumor Size ≤ 1 cm and Node Negative Breast Cancer.
Authors: Shao T , Boolbol SK , Boachie-Adjei K , Klein P 
Published: June 2012

Abstract
Background
Data regarding the clinical significance of HER2 and triple negative status in patients with small node negative tumors is limited. Several small case series have suggested an increased risk of recurrence in patients with T 1abN0M0 HER2+ or triple negative (TN) tumors. Conversely, a recent study reported that the recurrence risk for T1abN0M0 HER2+ tumors was too low to justify any adjuvant chemotherapy or trastuzumab. Therefore it remains unclear who among those with small lesions might possibly benefit from more aggressive adjuvant therapy.
Methods: We identified all node negative breast cancer patients with tumor size ≤ 1 cm diagnosed between 1/1/1995 and 12/21/2008 through our institutional breast service database. Patients were classified according to their receptor status into three groups: 1) Hormone receptor (HR)+ (ER or PR positive, HER2 negative); 2) HER2+ (IHC 3+ or FISH ≥2); and 3) TN (ER, PR, and HER2 negative). Disease-free survival (DFS) was calculated using KaplanMeier methods. Cox proportional hazards models were used to estimate the association between breast cancer subtypes with DFS adjusting for patient and disease characteristics.
Results: Among 658 patients with tumor ≤ 1 cm, 494 (75%) of the patients were HR+, 109 (17%) were HER2+, and 55 (8%) were TN. Two hundred thirty-two tumors were classified as T1a, and 426 were classified as T1b. Median age was 58 years (27-92). Median follow-up was 3.5 years. The 5-year DFS rates were 97.9%, 95.6%, 93.5% in patients with HR+, HER2+, and TN tumors, respectively (p=0.026). In multivariate analysis, TN status was associated with worse DFS (HR 3.13, 95% CI 1.26−7.73), while HER2+ was not (HR 1.64, 95% CI 0.73−3.69). In the HER2+ group, 5-year DFS was also not different between patients who received chemotherapy +/− trastuzumab (32%) and those who did not (p=0.588). We also analyzed T1aN0 and T1bN0 patients separately in order to differentiate the sub-populations of patients more likely to benefit from systemic adjuvant chemotherapy. TN status remains an independent risk factor for worse DFS in T1bN0 (HR 3.68, 95% CI 1.17−11.6), but not in T1aN0 patients.
Conclusion: TN, but not HER2+ status was associated with worse DFS in patients with T1abN0M0 tumors, and adjuvant chemotherapy should be considered in TN breast cancer patients who have T1bN0 tumors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-03.
P4-10-01: Tumor Markers Predicting Recurrence Type after a Primary Ductal Carcinoma In Situ.
Authors: Zhou W , Johansson C , Jirström K , Ringberg A , Blomqvist C , Amini R-M , Fjällskog M-L , Wärnberg F 
Published: June 2012

Abstract
Background: The risk for recurrence after a primary ductal carcinoma in situ (DCIS) is approximately 8% after ten years. If a recurrence occurs, the risk of the recurrence being invasive is approximately 50%. However, the knowledge of determinants for type of recurrence is limited. The purpose of this study was to investigate the predictable effect of specific biologic markers on the type recurrence after a primary DCIS.
Material and Methods: All women diagnosed with a primary DCIS between 1986 and 2004 in Uppsala and Västerås, Sweden were included (n=458). We also included all women from the SweDCIS Trial with a known recurrence (n= 166). TMA blocks were constructed and immunohistochemistry (IHC) was used to evaluate the status of estrogen receptor (ER), HER2, epidermal growth factor receptor (EGFR/HER1), cytokeratin 5/6 (CK 5/6), forkhead box A1 (FOXA1), forkhead box C1 (FOXC1), Ki 67, CD 10 and transacting T-cell-specific transcription factor GATA-3 (GATA-3) in the primary DCIS tumors. Logistic regression was employed to calculate the difference of expression status of biological markers between groups. Odds ratios (ORs) and 95% confidence interval (CI) were calculated, with adjustment for age, free margins, surgical type and molecular subtype by IHC.
Results: Of the 624 patients, 358 without recurrence were grouped as controls. Of the 266 with recurrence, 130 developed an in situ recurrence, while the remaining 136 developed invasive recurrence. Mastectomy compared to breast conserving surgery (BCS) and free margins were associated with less recurrences (OR 0.07, 95% CI 0.03 — 0.15) and (OR 0.39, 95% CI 0.26 — 0.58). As compared with the most common molecular subtype Luminal A, the subtype Luminal B had statistically significant higher risk of recurrence (OR 2.01, 95% CI 1.12 — 3.59). Higher risk of all recurrences was also observed for FOXA1 (OR 3.16, 95% CI 1.48 — 4.74) and FOXC1 (OR 2.39, 95% CI 1.39 — 4.09). In the analyses of type of recurrence, ER-negative, HER2−positive and EGFR-positive tumors recurred more often as in situ; (OR 2.34, 95% CI 1.17 — 4.71), (OR 2.08, 95% CI 1.11 — 3.88) and (OR 2.20, 95% CI 1.11 — 4.36). The molecular subtype HER2+ was also associated with a lower risk of invasive recurrence (OR 0.27, 95% CI 0.11 — 0.67).
Conclusion: As expected, mastectomy and free margins were associated with a lower risk of recurrence. Molecular subtype Luminal B and tumor markers FOXA1 and FOXC1 had a higher risk of recurrence. Recurrences after molecular subtype HER2+, ER-negative and EGFR-positive DCIS were more often of the in situ type.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-01.
P4-11-11: Thyroid Disease Is Associated with Breast Cancer: A Meta-Analysis.
Authors: Hardefeldt PJ , Eslick GD , Edirimanne S 
Published: June 2012

Abstract
Background: The controversial relationship between benign thyroid diseases and breast cancer has been investigated for over 50 years. Despite extensive population studies, the results as a whole have been inconsistent. The purpose of this study was to collate and analyse available data, calculating a pooled odds ratio of the risk of breast cancer in patients diagnosed with benign thyroid diseases.
Materials and Methods: Studies were obtained from a database search of MEDLINE, EMBASE, PubMed, Current Contents and Google Scholar with additional cross checking of reference lists. Inclusion criteria required a confirmed diagnosis of a benign thyroid disease, reporting of an odds ratio or data to calculate an odds ratio (and 95% confidence interval) and the use of an internal control group as the comparator. Collated data was assessed for heterogeneity and a pooled odds ratio calculated. From 276 citations identified in this search, a total of 28 studies were identified meeting our inclusion criteria. No language restrictions were used in the search or study selection. All data were analysed using a random effects model.
Results: There was significant evidence of an increased risk of breast cancer in patients with auto-immune thyroiditis, evident in a pooled odds ratio (OR) of 2.92 (95% CI: 2.13−4.01). No heterogeneity was present (I2=0, p=0.62) and there was no publication bias (p=0.15). In addition, the results supported an increased risk associated with the presence of anti-thyroid antibodies (OR 2.02, 95% CI: 1.63−2.50) and goitre (OR 2.19, 95% CI: 1.44−3.33). Moderate but non-significant heterogeneity was present in the analysis of goitre (I2=49.2, p=0.08), while the risk of publication bias was not signigicant (p=0.08). In the analysis of antibody presence, moderate and non-significant heterogeneity was evident (I2=58.3, p=0.08) with no publication bias (p=0.07). Subgroup analysis of antibody presence revealed increased risk associated with both anti-TPO (OR 2.64, 95% CI: 1.82−3.83) and anti-Tg antibodies (2.71, 95%CI: 1.58−4.69). No heterogeneity was present in the analysis of either subgroup evident in an I2 index of 29.3 (p=.22) and 18.1 (p=0.30), respectively. Publication bias was not significant (p=0.53 and 0.17). Quantitative analysis of hypothyroidism and hyperthyroidism was not significant, evident in pooled odds ratios of 1.56 (95% CI: 0.78−3.12) and 1.56 (95% CI: 0.84−2.88), respectively. Heterogeneity was high in hypothyroidism (I2=80.9, p=0.001) yet minimal in hyperthyroidism (I2=0, p=0.75). Publication bias was not significant in either hypothyroidism (p=0.06) or hyperthyroidism (p=0.20).
Conclusion: While these results indicate a link between thyroid auto-immunity and breast cancer, further prospective studies are required to definitively prove causality.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-11.
P4-11-13: Influence of Two Years of Exemestane on Bone Mineral Density in Postmenopausal Women at Increased Risk of Developing Breast Cancer; a Companion Study to the NCIC CTG MAP.3 Trial.
Authors: Goss PE , Richardson H , Ingle JN , Chlebowski RT , Fabian CJ , Garber JE , Sarto GE , Hiltz A , Tu D , Cheung AM 
Published: June 2012

Abstract
Background
Exemestane significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk for breast cancer in the NCIC CTG MAP3 trial with no serious toxicities, including excess fractures or osteoporosis.
Purpose: To provide additional information on the effect of exemestane on bone loss in women at high risk for breast cancer, within a subset of women participating on the NCIC CTG MAP.3B study. The primary hypothesis is that exemestane does not induce clinically significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years. The primary objective of this companion study is to examine the effect of exemestane on lumbar spine and total hip BMD by DEXA at 2 years in women participating in the MAP3 trial.
Methods: The MAP.3B bone sub-study registered women from the main MAP. 3 trial from May 2008 to March 2010. Eligible women had to have an acceptable quality BMD scan by DEXA taken within 12 months prior to randomization to MAP.3. A BMD T-score &gt;-2.0 SD (i.e. better than 2 standard deviations below the average peak BMD of a young adult woman) was established as the study population cutoff. A questionnaire including information on height, falls, fractures, lifestyle information including physical activity, tobacco and alcohol use was completed at baseline, 12 months, 24 months and at last visit. Fasting serum for bone biomarkers was collected at 12 months and total hip and L1-L4 (postero-anterior) spine BMD were measured 2 years after randomization on the same Lunar or Hologic scanner. The primary objective was to determine differences in hip and spine BMD at 2 years. Secondary outcomes include number of skeletal fractures and development of osteoporosis 2 years after randomization and changes in bone biomarkers at 1 year after randomization. For the analysis of the primary endpoints, the upper limit of a one sided 95% confidence interval for the difference in mean percentage changes between placebo and exemestane will be calculated for the BMD by DEXA at each site. We will conclude that exemestane does not induce significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years when the upper limit is less than 3% for both sites. Similar confidence interval approach will be used to analyze the secondary endpoints.
Results: Between May 2008 and March 2010, 238 postmenopausal women were recruited. Median age was 61.8 years, and the majority of women were Caucasian (91%), with approximately 20% of the participants reporting a recent fall (within past 12 months) and another 13% reporting a recent fracture prior to randomization. We will report results from the primary as well as the secondary endpoints at the SABCS meeting.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-13.
P4-11-15: Increased Propability of Triple Negative Breast Cancer (TNBC) in Premenopausal Patients after Exogenous Hormonal Intake (EHI).
Authors: Pistamaltzian NF , Tzavara C , Papadimitriou C , Gyftaki R , Tryfonopoulos D , Panopoulos C , Tsoukalas N , Koumakis G , Demiri S , Koufopoulos N , Misitzis Y , Apostolikas N , Efremidis A 
Published: June 2012

Abstract
Purpose: HRT is a known risk factor for breast cancer (BC) among post-menopausal women. Our knowledge in relation to EHI (estrogens and/or progestin) and BC among pre-menopausal women is scarce. We have studied whether previous EHI influences BC phenotype, clinical and pathologic characteristics and correlation with other known BC risk factors.
Patients and methods: A prospective analysis (data recorded upon patients first presentation) of an electronic database at a tertiary cancer centre was performed. Patients’ demographics, risk factors for BC (smoking, alcohol use, obesity, family history), clinical profile, EHI parameters (duration, cause) and the tumors’ histopathology (type, grade,ER/PgR and HER2 by IHC and FISH) were analyzed. Premenopausal patients without an EHI history consisted control group.
Results: Out of 938 patients treated for BC between 2006 and 2010, 333(35,5%) were premenopausal and 131(39%) of them reported any use of hormones. Median age was identical (43 years,range:20–57) among premenopausal patients with and without EHI history. Mean duration of use was 28 months (range:1–180). Causes of EHI were contraception (35%), pregnancy(17%), menstrual abnormalities(17%) and medically assisted fertilization(17%). Smoking, alcohol use and obesity didn't differ among two groups. Family history for BC was more common (31, 3% vs. 22,8%, p=0,08)among women with EHI. No correlation was found among duration of use and the time of cancer diagnosis, while the mean time from the cessation of hormones to cancer diagnosis was 13 years(range:1–32). Only 18% of breast cancers were diagnosed within the first 5 years after exogenous hormones cessation.
TNBC was found to be significantly increased among premenopausal women with a history for EHI (23,6% vs. 13,4%, p=0,016). This increase was independent of the existence of positive family history for BC (p=0,61). EHI conferred a twofold increase in the risk for a TNBC (OR=1,99 p=0,019). No other clinical or histopathologic parameter showed any difference among the two groups.
Conclusion: Prior use of exogenous hormones, for any cause and irrespective of the coexistence of other risk factors and family history, increases the probability of a triple negative breast cancer diagnosis by twofold. Whether this represents a trend of a changing epidemiology in the types of BC in prior hormone users vs. nonusers, poses an extremely challenging hypothesis to be verified in large epidemiologic studies — given the young age and the treating difficulties of this patient population.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-15.
P4-11-17: Noninferiority (NI) Phase III Trials in Advanced Breast Cancer (ABC) over 12 Years.
Authors: Saad ED , Militao MS 
Published: June 2012

Abstract
Background
NI trials have gained increasing importance in oncology. The contemporary practice regarding the design features and the results of NI trials have not been formally assessed in ABC.
Methods: We searched PubMed for articles reporting the efficacy results of phase III trials on systemic antineoplastic treatments for ABC published between 1/1998 and 12/2009 in 11 leading medical journals (Ann Oncol, BCRT, BJC, Cancer, CCR, EJC, JCO, JNCI, Lancet, Lancet Oncol, and NEJM).
Results: We retrieved 93 reports, 12 of which (13%; 95% CI, 7% — 22%) had a NI primary hypothesis. Of note, there were no equivalence (i.e., two-sided question) studies. There was no significant trend in the proportion of NI trials in the two 6-year periods compared (17% vs 9%; P=0.36). The median (range) sample sizes for NI and superiority trials were 404 (160-1354) and 326 (118-907) patients, respectively (P=0.32). NI trials enrolled exclusively first-line patients more frequently than superiority trials (83% vs 51%; P=0.06). The primary endpoint for NI trials was response rate (RR) and progression-free survival/time to tumor progression in 8 and 4 cases, respectively. Despite their nominally higher number of patients, NI trials were more likely than superiority trials to have RR as their primary endpoints (67% vs 32%; P=0.03). The NI margin was reported in all trials, but justified by authors in only one case. Among trials with RR as primary endpoint, the NI margin was 15% in six cases and 25% in two. In trials with progression-free survival/time to tumor progression as primary endpoints, the lower limit of the confidence interval for the hazard ratio to demonstrate NI was always 0.8. Of 12 NI trials, 9 were positive (i.e., proved NI).
Conclusion: NI trials represent 13% of contemporary phase III trials on ABC. Most such trials achieve their primary endpoint. At present, NI margins seem to be chosen on historical basis rather than on statistical reasoning, and such choice could bear implications on trial positivity.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-17.