bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD07-04: Predicting Outcome with Ki67 in Primary Breast Cancer in the Neoadjuvant Setting
Authors: Li SP , Burcombe R , Beresford MJ , Kornbrot DE , Seah M-L , Ostler PJ , Wilson GD , Makris A. 
Published: April 2011

Abstract
Background: The proliferation antigen Ki67 has been shown to be a reliable predictive marker of treatment efficacy in the neoadjuvant treatment of breast cancer but its prognostic significance remains uncertain. This study assesses Ki67 before and after neoadjuvant chemotherapy (NAC) in relation to long-term outcome. Methods: 117 patients with primary breast cancer due to undergo NAC were studied (median age 48 years, range 25-78; T2-4, N0-3, M0) and information gathered from a prospectively maintained database. Immunohistochemically derived Ki67 expression was obtained from pretreatment core biopsy and surgical specimens. Their relationship to DFS and OS was analyzed along with known prognostic variables (age, ER/PR/HER2 status, clinical and pathologic T and N stage, grade), NAC regimen, response and adjuvant treatment. Survival curves were estimated using the Kaplan-Meier method and a log-rank test used to determine significance using a two-tailed p-value of 0.05. A multivariate Cox proportional hazards regression model performed in a stepwise fashion was used to determine the prognostic value of each signifcant variable. Results: 84 patients with matched biopsy and surgical samples were assessable for pre and post NAC Ki67 levels. The majority (90%) received anthracycline based NAC (median number of cycles 6, range 2-6). On univariate analysis, the only significant pretreatment predictive factor for shorter DFS was higher clinical nodal stage (cN) (P&lt;0.001). Posttreatment variables that predicted for worse DFS were: Ki67 at surgery (HR 1.52, p=0.048), pathologic nodal stage (pN) (p=0.001) and grade (p=0.013). On multivariate analysis, pN was the most powerful predictor for DFS (chi-squared test 19.8, 3 df, P&lt;0.001). Univariate analysis of pretherapy factors for OS revealed that Ki67 at biopsy (HR 2.06, p=0.039), cN (HR 4.44, P&lt;0.001) and PR positivity (HR 0.41, p=0.012) were significant. Significant posttreatment variables for OS were Ki67 at surgery (HR 2.01, p=0.006), pN (p=0.001), and grade (p=0.009). PR status and pN remained important predictors of OS on multivariate analyses. Conclusions: The expression of Ki67 is a widely accepted marker of cellular proliferation in breast cancer. Ki67 levels after NAC were a better predictor for long-term outcome than pretherapy Ki67, although nodal status appears to be the most powerful determinant overall. High Ki67 levels post NAC may identify patients with poorer outcomes who are candidates for further systemic therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-04.
Abstract PD07-08: Integrated Genomic Analysis before and after Brief Exposure to Trastuzumab (T): The11q13 and 17q12 Amplicons Are Associated with Response to T+Chemotherapy in Early Stage HER2 Positive Breast Cancer
Authors: Harris LN , Liu Z , Li A , Sprecher E , Sarkar S , Lezon-Geyda K , Krop I , Winer EP , Tuck DP. 
Published: April 2011

Abstract
Background: The receptor tyrosine kinase HER2 is overexpressed in 18-20% of breast cancers and is the target of the highly effective therapy, trastuzumab. Coamplicons are frequent in HER2 amplified tumors, yet their role in response to T is not defined. To identify amplicons which might predict response to T in patients we performed gene expression and copy number analysis in tumor tissue from a preoperative trial with brief exposure to T, followed by T+C.
Methods: Fresh tumor core biopsies were taken before at a 2 week timepoint after a single dose of T (8mg/m2) from 80 HER2-overpressing, early breast cancer patients enrolled on a clinical trial of T&gt;T+C. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina Ref8 and Illumina QUAD 610 SNP arrays. Eight commonly amplified regions (11q13, 14q32, 17q12, 20q13, 21q22, 8p22, 8q24) were identified by FISH probe coordinates and copy number calculated using the GPHMM algorithm. Amplification was defined as 4 or more copies of the amplicon. Gene expression was analyzed in Bioconductor using LIMMA analysis. Genomic biomarkers were compared pathologic complete response (pCR) vs objective response (CR+PR) and non-response (SD+PD) by RECIST criteria at the surgical timepoint.
Results: There were 50 tumor pairs with adequate RNA for gene expression and 40 baseline tumors for copy number analysis with 28 paired samples. In the 40 baseline biopsies, the 11q13 amplicon was present in 14/40 (35%) of tumors but never seen in tumors with a pCR (t-test; p=0.004975). Of note, in the tumors with amplification of 11q13 there was no evidence of change in copy number after exposure to T, however numbers were small (7 pairs). Gene expression of the 11q13 region showed no significant change in common amplicon genes after one dose of T. The 17q12 amplicon, which harbors the HER2 locus, was amplified in 35/40 (87.5%) of cases - copy number was not associated with response, however, HER2 and GRB7 gene expression levels significantly declined in pCR tumors compared with &lt;pCR (p=0.003).
Conclusions: Integrated genomic analysis after brief exposure to T may provide useful predictors for response to T+C in early stage, HER2 positive breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-08.
Abstract PD09-03: Disease Outcomes in Primary Breast Cancer Are Associated with Obesity, Lymph Node Status and Angiolymphatic Invasion
Authors: Vona-Davis L , Turner JM , Gadiyaram V , Hobbs G , Ducatman B. 
Published: April 2011

Abstract
Background: Obesity is associated with higher rates of breast cancer and poorer survival. Our previous work has shown that lymph node metastases are more frequently associated with advanced disease in obese patients. We sought to investigate the association of obesity with angiolymphatic invasion on disease outcomes in patients with invasive breast cancer. Methods: This retrospective study involved 627 predominately white women with invasive breast cancer. Hospital tumor registry, charts, and pathology records provided demographics and tumor biologic features. Body mass index (BMI) values were categorized according to WHO criteria: normal or underweight (lean), &lt; 25.0 kg/m2; overweight, 25.0 to 29.9 kg/m2; obese, 30.0 kg/m2 or higher. Univariate and multivariate analyses were conducted between BMI and clinical outcomes, controlling for menopausal status. Recurrence-free survival and overall survival were calculated and a log-rank test was used to determine significance between groups.
Results: In our study cohort, 175 (27.9%) were normal weight, 211 (33.7%) overweight and 241 (38.4%) were considered obese. Greater lymph node involvement and angiolymphatic invasion (P = 0.04) were present with obesity. Triple-negative tumors were more common in those patients classified as overweight and obese (43%) compared to normal weight individuals (20%). Factors associated with BMI were tumor size and lymph node status. In postmenopausal women, obesity was associated with an increased risk of lymph node metastases (OR 1.81, 95% CI 1.14-2.91; P = 0.010) and angiolymphatic invasion (OR 2.09, 95% CI 1.01-4.72; P = 0.049) when compared with normal weight individuals. The probability of developing a relapse within 10 years was higher among women with BMI ≥30.0 with positive lymph nodes and the presence of angiolymphatic invasion.
Conclusions: In obese women with breast cancers, higher rates of lymph node involvement and angiolymphatic invasion may explain poorer outcomes. These findings further support the relationship between obesity and the factors that are elaborated by adipocytes as instrumental in promoting a more aggressive growth and progression of breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD09-03.
Abstract PD09-05: Impact of Body Mass Index (BMI) on the Efficacy of Endocrine Therapy in Postmenopausal Breast Cancer Patients — An Analysis of the ABCSG 6 and 6a Trial
Authors: Pfeiler G , Stöger H , Singer C , Seifert M , Jakesz R , Dubsky P , Samonigg H , Greil R , Menzel C , Heck D , Gnant M. 
Published: April 2011

Abstract
Background: Recently, we have demonstrated that BMI significantly impacts on the efficacy of anastrozole but not tamoxifen (TAM) in premenopausal breast cancer patients. As aromatase inhibitors (AIs) are a mainstay in the treatment of endocrine responsive postmenopausal breast cancer patients, it is of certain interest, if this influence of BMI on endocrine therapy is also true for the postmenopausal situation. Methods: For analysis of the ABCSG 6 and 6a trial, patients were classified as normal weight (BMI 18.5-24.9 kg/m2) or as overweight (BMI ≥25kg/m) according to WHO criteria. The underweight population was excluded from the analyses.
We retrospectively analysed the ABCSG 6 trial, which examined the efficacy of TAM versus TAM + aminoglutethimide (first generation AI) in endocrine responsive postmenopausal breast cancer patients. All patients have been censored after 60 months since the majority of patients without events have been re-randomized into trial ABCSG 6a after 5 years. Further, we retrospectively analysed the ABCSG 6a trial, which examined 3 additional years of anastrozole versus no further treatment after 5 years of endocrine treatment.
Results: 1,566 patients (311 events/214 deaths) and 477 patients (108 events/64 deaths) were included in the analyses of the ABCSG-6 trial and the ABCSG-6a trial, respectively. About two thirds of all patients in both trials were overweight and one third was normal weight. Analysing the ABCSG 6 trial, no difference in disease free survival (DFS) and overall survival (OS) between normal weight and overweight patients treated with TAM versus TAM + aminoglutethimide could be observed. Analysing the ABCSG-6a trial, normal weight patients treated with anastrozole showed a remarkable and significant reduced risk in DFS and OS compared to control (HR 0.464, 95%CI 0.242 0.842 p=0.02 and HR 0.372, 95%CI 0.16 0.863, p=0.02). In contrast, in overweight patients anastrozole compared to control did not improve DFS and OS (HR 0.991, 95%CI 0.611 1.608, p=0.97 and HR 0.871, 95%CI 0.456 1.662, p=0.67). Conclusion: BMI impacts on the efficacy of anastrozole but not tamoxifen in postmenopausal breast cancer patients. It seems that overweight patients in contrast to normal weight patients do not benefit from additional 3 years of anastrozole after 5 years of endocrine therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD09-05.
Abstract PD10-06: Concordance in Hormone Receptors and HER2 Expression between Primary Breast Cancer, Loco-Regional Recurrences and Distant Metastases. Subgroups Analysis and Predictors of Discordance
Authors: Petracci FE , Costanzo MV , Nervo AA , Nadal J , Amat M , Domenichini E , Chacón RD. 
Published: April 2011

Abstract
Background. Retrospective reviews and small prospective studies have shown that hormone receptor (HR) and HER2 status may change between primary breast cancer and recurrences in 15 to 40% and 0 to 34% respectively. This may lead to changing treatment in 15 to 20% of patients (pts). The primary aim of this study is to evaluate the discordance in HR and HER2 status between primary tumors, loco-regional recurrences (LRR) and distance metastasis (mets, DM). Secondary objective is to identify predictors of discordance.
Patients and Methods. Retrospective analysis of patients with invasive breast cancer with biopsy of suspicious metastatic lesion. HR status (estrogen and/or progesterone) was defined as positive (HR+ve) when immunohistochemistry (IHC) staining was ≥10% of cells. HER2 positive (HER2+ve) was defined by IHC 3+ or amplified by fluorescence in situ hibridization (FISH).
Results. Two hundred and fifty one pts were evaluated with two hundred biopsies available for analysis. Median follow-up was 77 months (range, 2.5 — 415.1). 59% of primary tumors were HR+ve/HER2-ve, 27% triple negative (TN), 9% triple positive (TP) and 5% HR-ve/HER2+ve. 75.5% of patients received adjuvant chemotherapy, 5.0% primary chemotherapy, 78% adjuvant radiation and 44% hormonal therapy. 12 pts developed secondary breast cancer before recurrence. 50% (131) of recurrences were LRR and 50% were DM (17% visceral, 27% non-visceral and 2% central nervous system mets). LRR or DM surgery was performed in 33% of patients. We observed a 21% of discordance for HR (18% negative to positive and 28% positive to negative) and 6% of discordance for HER2 (5% negative to positive and 6% positive to negative). The overall discordance in HR/HER2 subgroups was 22%. No statistical differences (p .27) were observed in HR/HER2 subgroups’ discordance between LRR (median time to LRR, 43.5 months) and DM (median time to DM, 58 months). Greatest discordance was seen in TN tumors (31%), follow by HR-ve/HER2+ve, TP and HR+ve/HER2-ve with 28.5%, 25% and 17% respectively. Neither of TP tumors nor of 3 patients treated with trastuzumab became negative for HER2. At multivariate analysis, recurrence free interval longer than 24 months was the only statistical predictor of discordance (p .02).
Conclusions. Considering the high percentage of receptors status discordance and current options of systemic treatments, including target therapies, tissue confirmation and HR/HER2 analysis should be recommended for patients with suspicious of loco-regional or distant mets.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-06.
Abstract PD10-07: Hormone-Receptor Expression and Activity of Trastuzumab-Based Therapy in HER2-Positive Advanced Breast Cancer Patients
Authors: Montemurro F , Rossi V , Cossu Rocca M , Martinello R , Verri E , Redana S , Adamoli L , Valabrega G , Sapino A , Aglietta M , Viale G , Goldhirsch A , Nolè F. 
Published: April 2011

Abstract
Background: Hormone receptors (HR) and the human epidermal growth factor receptor 2 (HER2) are key biological factors in breast cancer. Gene expression profile studies indicate that HER2-positive/HR-positive and HER2-positive/HR-negative tumors fall into two distinct subtypes. These two subtypes carry a different prognosis in the absence of HER2-targeting. Furthermore, a relationship has been documented between increasing HR expression and reduced chemoresponsiveness. Despite these differences, HER2-positive abvanced breast cancer patients are usually treated with a unified approach of combining chemotherapy with an HER2-targeting agent, regardless of HR status. We studied the association between hormone receptor (HR) expression and the clinical outcome of women with HER2-positive advanced breast cancer receiving chemotherapy plus trastuzumab.
Methods: The effect of HR expression on overall response rate (ORR) and progression-free survival (PFS) to trastuzumab-based treatment was studied by univariate and multivariate analysis. HR positivity was defined as 1% or more tumor cells positive for the estrogen (ER) and/or for the progesterone (PgR) receptor by immunohistochemistry. For both ER and PgR, we studied different thresholds to identify levels of expression associated with the clinical outcomes of interest.
Results: 227 consecutive advanced breast cancer patients receiving trastuzumab plus chemotherapy between June 1999 and November 2008 at two Institutions were retrospectively analyzed. One hundred eleven patients (49%) had HR-positive tumors. Compared with low or no expression, high expression of ER (30% or more) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio 0.422, 95% confidence interval-C.I. 0.222-0.803, p = 0.009). In patients with HR-positive tumors the addition of maintenance endocrine therapy to trastuzumab after the completion of chemotherapy was associated with a significant increase in progression-free survival (hazard ratio-HR 0.521, 95% C.I. 0.3325-0.836, p = 0.007). Patients with HR-positive tumors not receiving maintenance endocrine therapy had similar PFS than patients with HR-negative tumors (HR 0.914, 95% C.I. 0.654-1.279, p = 0.601). In patients not receiving maintenance endocrine therapy, high ER expression (30% or more cells) was associated with non-significant trend towards reduced risk of progression, compared with patients with low or absent ER expression (HR 0.747, 95% C.I. 0.516-1.081, p = 0.122). Conclusions: Our results suggest a predictive role of HR expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy and endocrine therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-07.
Abstract S2-4: Final Results of a Prospectively Planned Biomarker Analysis: HER1-3 as Predictive Markers of Benefit from Early Treatment with Aromatase Inhibitors Versus Tamoxifen in the TEAM Pathology Sub-Study.
Authors: Bartlett JMS , Brookes CL , van de Velde CJH , Stocken D , Campbell FM , Hasenburg A , Kay C , Kiebeck D , Markopoulos C , Meershoek-Klein Kranenbarg E , Mallon EA , Dirix L , Robson T , Seynaeve C , Rea DW. 
Published: April 2011

Abstract
Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included prospectively planned biomarker studies to identify predictive biomarkers for patients receiving endocrine therapy. Quantitative IHC data for ER/PgR, HER1, HER2, HER3 and FISH analysis of HER2 in all cases was available for the current analysis relative to outcome of estrogen receptor-positive (ER+) early breast cancer patients treated with exemestane versus tamoxifen.
Patients & Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. Quantitative analysis of receptors (HER1/2/3) by conventional IHC, and FISH (for HER2 only) were analysed relative to disease-free survival and treatment on an intent to treat basis using survival data for the first 2.75 years of the TEAM trial. Results: Of 4595 eligible cases samples received, 16 were excluded, and 4010 had complete biomarker data for all markers (HER1/HER2 & HER3) for the final biomarker analysis, 3.5% were HER1 positive, 13% HER2 positive & 21% HER3 positive. 1248 (31%) cases were HER1or2or3 positive (HER1-3+ve). HER1-3 positivity was associated with poor outcome (HR=1.6 95%CI=1.3-2.0). In HER1-3 negative patients the hazard ratio (for risk of relapse on exemestane versus tamoxifen in the first 2.75 years) was 0.68 (95% CI = 0.52-0.89), for the HER1-3 positive cases the hazard ratio was 1.14 (95% CI = 0.83-1.56) with a significant treatment by marker interaction (HR=1.68 95%CI=1.1-2.5; p=0.0014 in multivariate analysis). Trends for similar effects were seen for HER1 negative (-ve) vs HER1 positive (+ve) (HRs 0.80, 95%CI=0.65-0.99 vs 1.63 95%CI=0.74-3.59), HER2-ve vs HER2+ve (HRs 0.71, 95%CI=0.57- 0.9 vs 1.69 95%CI=108-2.63) and HER3-ve vs HER3+ve (HRs 0.78 95%CI=0.62-0.99 vs 1.04 95%CI=0.67-1.62) breast cancers. Conclusion: Preferential exemestane versus tamoxifen treatment benefit was seen in HER1/2/3 negative cases, whilst HER1/2/3 positive cases had a poor prognosis in this endocrine treated population (suggesting a degree of resistance to endocrine therapy), and no evidence of additional benefit from AIs versus tamoxifen. These three Type I receptor tyrosine kinases appear to identify breast cancers with relative resistance to all forms of endocrine therapy. This prospectively planned and powered treatment by marker analysis provides high level scientific evidence which may assist clinicians and patients in determining optimal AI schedules for women with early breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-4.
Abstract S3-2: Neoadjuvant Pertuzumab (P) and Trastuzumab (H): Antitumor and Safety Analysis of a Randomized Phase II Study ('NeoSphere')
Authors: Gianni L , Pienkowski T , Im Y-H , Roman L , Tseng L-M , Liu M-C , Lluch-Hernandez A , Semiglazov V , Szado T , Ross G. 
Published: April 2011

Abstract
Background: P binds to HER2 and has complementary mechanisms of action with H. A clinical study of P+H showed meaningful activity in patients (pts) with metastatic HER2-positive breast cancer whose disease progressed on prior H therapy (Baselga et al. JCO 2010). NeoSphere is a Phase II randomized trial of preoperative systemic therapy comparing H and docetaxel (TH), THP, HP and TP to rank antitumor activity and tolerability.
Methods: 417 pts with centrally-confirmed HER2-positive (IHC 3+ or FISH positive) breast cancer (stage II or III including locally advanced) were randomized to receive 4 cycles of TH (n=107), THP (n=107), HP (n=107), or TP (n=96) before surgery. Cycles were given intravenously q3w: P, 840 mg loading dose and 420 mg maintenance; H 8 mg/kg loading dose and 6 mg/kg maintenance; T, 75 mg/m2 with escalation to 100 mg/m2 if the starting dose was well tolerated. After surgery all pts received H to 1 year and 3 cycles of FEC; in case of neoadjuvant HP they also received T before FEC. The primary endpoint was rate of pathological complete response (pCR) in the breast. For all patients, a tissue sample at baseline, as well as at surgery following 4 cycles of neoadjuvant therapy, was collected for biomarker analyses.
Results: Baseline characteristics were well balanced. About 40% of patients had locally advanced/inflammatory breast cancer. In the intent-to-treat analysis the rates of pCR and clinical objective response in the breast were:
pCR for THP was significantly higher (p=0.014) than TH which was significantly higher than HP (p=0.031). Clinical disease progression was reported in 1 patient on TH and 2 patients on HP. Feasibility was good for all T-containing arms. Adverse events of grade ≥3 were rare (&lt;7%) with HP in sharp contrast with the &gt;50% incidence in T-containing arms. One pt developed congestive heart failure with HP. Five more patients had asymptomatic decreased LVEF with TH (1), THP (3) and TP (1) that resolved at the subsequent assessment. Biomarker analysis is ongoing. Conclusions: These data show the superior antitumor activity of THP and very favorable therapeutic ratio for HP that justify continuing study of the two monoclonals with and without docetaxel in women with HER2- positive early or metastatic breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-2.