bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PD05-06: Is ERα a Tamoxifen Predictive Factor in ERα Negative Breast Cancer in Premenopausal Women?
Authors: Källström A-C , Fernö M , Jönsson PE , Landberg G , Nordenskjöld B , Stål O.
Published: April 2011

Background: The majority of breast cancers are hormone receptor positive, defined as estrogen receptor (ERα) and/or progesterone receptor (PR) positive. Adjuvant tamoxifen decreases the risk of recurrence and improves survival in hormone positive breast cancer, irrespective of age. Still some do not respond to tamoxifen. The clinical significance of ERα is still unclear, even if studies indicate that ERα might be of importance. The aim of this study was to investigate the tumor expression of ERα in premenopausal women with breast cancer and the relationship to other clinical and pathological parameters and if there is any prognostic or predictive value. This is the first study of ERα based on a randomized study including only premenopausal women.

Material and Methods: Premenopausal women (n=564) with breast cancer, Stage II (UICC), were randomized to either two years of adjuvant tamoxifen (n=276) or no tamoxifen (n=288). The median follow-up was 13.9 years. The expression of ERα (n=303) and ERα (n=309) was analyzed by immunohistochemistry (IHC) using tissue microarrays (TMA). ERα was considered positive if more than 50% of the cells were stained (n=174). ERα was scored according to number of positive cells and the intensity of the staining. ERα negative (n=70) score 0, 1-49% (n=137) score 1, 50-100% (n=102) score 2 and the intensity negative (n=70) score 0, weak (n=119) score 1, strong (n=120) score 2. ERα summary score 4 was considered positive (n=118).

Results: ERα was correlated with lymph node status (p=0.024), ERα (p=0.00016), PR (p=0.0084), Ki67 (p=0.035), cyclin D1 (P>0.00001) but showed a negative correlation to HER2 (p=0.042). Patients with ERα+/ERα- tumors showed significant benefit from 2 years of tamoxifen compared to those with ERα-/ERα — tumors (table1). In the control group ERα showed no prognostic value.

Recurrence free survival (RFS) at 10 years tamoxifen vs control

Discussion: ERα might be a tamoxifen predictive factor in ERα negative premenopausal breast cancer. If so, further studies are motivated to explore whether a subset of patients with triple negative breast cancer could benefit from endocrine therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-06.
Abstract PD05-10: HOXB7 as a Key Regulator in the Development of Tamoxifen Resistance
Authors: Jin K , Bhujwalla ZM , Sukumar S
Published: April 2011

Multiple factors including long term treatment with tamoxifen are involved in the development of selective estrogen receptor modulator resistance of ERα positive breast cancer. It is well known in the endocrinology field that increased levels of ErbB/HER family members can also directly alter the cellular response to tamoxifen, but the mechanisms underlying increased expression of ErbB/HERs are not clear. In this report we show that HOXB7 is an ERα responsive gene and the downregulation of HOXB7 expression by estradiol is abrogated by tamoxifen in MCF7 cells. HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. EGFR and HER2 expression is upregulated by overexpression of HOXB7, while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of EGFR and HER2 expression and loss of tamoxifen resistance. In addition, our work demonstrates that to mediate upregulation of EGFR and HER2, HOXB7 binds to ER-alpha and promotes HER2 transcription activity through direct binding to the HER2 enhancer region by competing with other cofactors. Also, HOXB7 enhances EGFR transcription activity via binding to EGFR promoter region. However, depletion of HOXB7 affects the binding affinity of HOXB7 and the cofactors to the HER2 enhancer element. Higher expression levels of HOXB7 significantly correlated with poorer disease free survival in ERα positive breast cancer patients on adjuvant tamoxifen monotherapy. These findings implicate overexpression of HOXB7 as a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules in the oncogene heirarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-10.
Abstract PD06-02: Are Outcomes Really Similar after Lumpectomy and Mastectomy for Early Stage Invasive Breast Cancer? Evidence from Population-Based Data
Authors: Hwang ES , Gomez SL , Lichtensztajn D , Fowble B , Clarke CA.
Published: April 2011

Background: Randomized clinical trials have established equivalent survival for patients undergoing breast conserving therapy and radiation (BCT) compared to those undergoing mastectomy (M). However, these studies were conducted over two decades ago prior to the era of widespread systemic therapy and improved locoregional therapy and did not assess separately effects by age and tumor type types. We examined survival in a contemporary and representative series of women undergoing BCT or M without radiation for early stage (I-II) breast cancer to assess observationally whether survival varied by surgical treatment among age groups and tumor types.

Methods: We used the population-based California Cancer Registry supported by the NCI's Surveillance, Epidemiology and End Results (SEER) Program. We included women diagnosed with stage I and II breast cancer between 1990 and 2003, treated with either BCT or M, and followed for vital status for through the end of 2008. Overall survival (OS) and disease-specific survival (DSS) were compared between BCT and M groups using the Cox proportional hazards model, adjusting for tumor stage at diagnosis, tumor size, grade, number of positive nodes and race. Analysis was stratified by age group (<50 years and ≥50 years) and tumor estrogen receptor (ER) status.

Results: 139,430 women fulfilling eligibility criteria and 15,917deaths were identified in the cohort between 1990 and 2003; overall 5-year survival was 93.7% (95% CI 93.6-93.9%). 26% of the total cohort were <50 years of age at diagnosis; 62% were ER-positive. Stage at diagnosis, tumor size, grade, number of positive nodes and race differed significantly among the BCT and M groups. Adjusting for all of these factors, women undergoing BCT had a significantly lower hazard of mortality when compared to women who had M (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.79 - 0.89), with a more pronounced survival difference among women >50 (HR 0.76, 95% CI 0.73 — 0.79). This effect did not differ by ER status among women aged <50. However, among women aged ≥50, this effect was significantly stronger among ER(+) (HR 0.76, 95% CI 0.71-0.80) than ER(-) tumors (HR 0.81, 95% CI 0.75-0.89).

Conclusion: In a large, representative series of patients with early stage breast cancer, irrespective of age group or ER status, BCT was independently associated with a significant 19-32% improvement in OS. Although it is highly likely that at least some of this difference relates to unmeasured tumor characteristics or baseline health characteristics influencing treatment choice or overall survival, these findings are provocative and should be further explored in data resources with greater clinical detail.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-02.
Abstract PD06-07: Sentinel Node Biopsy Alone for Node Positive Breast Cancer, Report from the American College of Surgeon's National Cancer Database, 1998-2007
Authors: Yao K , Du H , Addie G , Winchester DJ , Barrera E , Jaskowiak N , Trocha S , Winchester DP.
Published: April 2011

Background: The decision to perform complete node dissection for a tumor positive sentinel node (SN) has become controversial especially in light of the results of a randomized trial of sentinel node biopsy alone for node positive disease. We report national trends in the United States of SN biopsy alone from 1998-2007 for node positive disease from the National Cancer Database (NCDB) of the American College of Surgeons. Patients and Methods: Utilizing the NCDB Participant User File we analyzed 994,883 patients diagnosed with invasive breast cancer from 1998 to 2007. Neoadjuvant cases and patients with clinically positive axillary nodes were excluded. All patients underwent breast surgery. After applying exclusion criteria, 104,548 SN tumor positive patients were identified. 15,643 (14.9%) patients underwent SN biopsy alone and 88,905 (85.1%) patients underwent SN biopsy followed by completion axillary node dissection. Cross tabulations with patient, tumor and hospital factors were performed.

Results: Over the 10 year period, there was a statistically significant increase in the number of patients undergoing SN biopsy alone, with 488 (9%) in 1998, and 1798 (17%) in 2007 (P<0.001), and similar pattern was seen across age (all p<.0001), income (all p<.0001), census region (all p<.001), tumor stage (all p<.01), and facility type categories (all p<.0001). Overall there was a significant increase in the number of patients undergoing sentinel node biopsy alone according to age, with 756 (10.2%) for patients ages 30 to 40 versus 1368 (24.2%) for patients ages 80 to 90 (P<0.0001). 7,149 (15.3%) of patients in the highest income range had SN biopsy alone versus 1387 (13.8%) in the lowest income range (p=0.0002). There were significant differences according to the census region with the highest rate for SN alone in the Northeast region, 1263 (21%) and lowest in the Atlantic region, 2116 (12.8%) (26.5%) (P<0.001). There were significant differences in SN biopsy alone according to tumor stage, with 14441 (16.8%) Stage II patients had SN alone versus 577 (3.5%) for those with Stage III tumors (P<0.0001). There were minimal differences in the facility type, with 2090 (15%) patients treated at a community cancer program had SN alone versus 8646 (15%) at a comprehensive community cancer program versus 4907 (14%) at an academic/teaching program (p=0.501).

Conclusions: The utilization of SN biopsy alone for patients with node positive breast cancer has significantly increased from 1998 to 2007. Patient age, tumor size, and socioeconomic status, were significant predictive variables but facility type was not.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-07.
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

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<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<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<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

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>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 <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

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), < 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

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

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

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

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

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 (<7%) with HP in sharp contrast with the >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.
Abstract S4-1: FinXX Final 5-Year Analysis: Results of the Randomised, Open-Label, Phase III Trial in Medium-to-High Risk Early Breast Cancer
Authors: Joensuu H , Kellokumpu-Lehtinen P-L , Huovinen R , Jukkola-Vuorinen A , Tanner M , Kokko R , Ahlgren J , Auvinen P , Bono P , Lindman H
Published: April 2011

Background: The randomised, phase III FinXX trial (NCT00114816) investigated whether the integration of capecitabine (X) into a sequential docetaxel (T)→cyclophosphamide + epirubicin + 5-FU (CEF) adjuvant regimen might improve clinical outcome for patients with medium-to-high risk early breast cancer. The planned interim analysis after a median follow-up of 3 years found a significant recurrence-free survival (RFS) benefit with the X-containing regimen versus control (3-year RFS rate: 93% XTP→ukkalaCEX vs 89% T→CEF; hazard ratio 0.66 [95% CI: 0.47-0.94]; p=0.020) [Lancet Oncol 2009;10:1145-51]. Here we present final 5-year RFS data, the primary endpoint of the study.

Methods: Eligible patients were aged 18-65 years, had a WHO performance status of 0 or 1 and histologically confirmed invasive breast cancer at medium-to-high risk of recurrence, defined as regional node-positive disease or node-negative disease with primary tumour diameter greater than 20mm and negative progesterone receptor assay. Previous neoadjuvant chemotherapy was not permitted. Patients were randomised in a 1:1 ratio to receive 3 cycles of T→3 cycles of CEF (T→CEF; T 80mg/m2 d1, q3w→C 600mg/m2 d1, E 75mg/m2 d1, F 600mg/m2 d1, q3w) or 3 cycles of XT→3 cycles of CEX (XT→CEX; X 900mg/m2 bid d1-15 + T 60mg/m2 d1, q3w→C 600mg/m2 d1, E 75mg/m2 d1, X 900mg/m2 bid d1-15, q3w). The primary endpoint was RFS, defined as the time from randomisation to the first time the patient is recorded as having disease recurrence or the date of death if the patient dies due to causes other than disease recurrence; secondary endpoints were overall survival and safety. Results: Between January 2004 and May 2007, 1,500 women from Finland and Sweden were randomised to T→CEF (n=747) or XT→CEX (n=753). Final analysis of the primary endpoint will be presented after a median follow-up of 5 years and approximately 200 events. Data are expected in October 2010.

Conclusions: The FinXX trial was the first to report the efficacy and safety of X in combination with anthracycline/taxane-containing therapy in the adjuvant treatment of early breast cancer. Final efficacy data are expected in October 2010.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-1.
Abstract S5-4: Synthetic-Lethality of Triple-Negative Breast Cancers Via the MYC Oncogene Pathway
Authors: Goga A , Horiuchi D , Kusdra L , Chandriani S , Lenburg ME , Gonzalez-Angulo AM , Huskey NE , Creasman KJ , Davis SE , Mills GB , Esserman LJ.
Published: April 2011

Background: Breast cancer lacking the estrogen, progesterone and ERBB2 receptors, (“triple-negative”) encompasses an aggressive sub-type that is associated with a higher incidence of early tumor recurrence and poor patient outcome, particularly after distant relapse. The lack of validated targets means that only conventional cytotoxic chemotherapy offers significant benefits, albeit with associated toxicities and lack of specificity. Among many potential therapeutic targets in triple-negative breast cancer, MYC may be important as its function is elevated in many breast cancers with aggressive phenotypes.

Methods: In this study we investigate the association between MYC abundance in primary breast tumors using two large clinical cohorts and examined MYC mRNA and protein abundance as well as the expression of a MYC gene signature. We next examined the association between the MYC gene signature and patient response to neoadjuvant chemotherapy as well as disease-free survival in the ISPY TRIAL. Furthermore, we examined whether high MYC expression in triple-negative tumors might provide a new therapeutic approach in this tumor sub-type. We tested a synthetic-lethal strategy to kill triple-negative breast cells with abundant MYC expression by inhibiting cyclin-dependent kinases (CDKs). Results: We find that human triple-negative breast cell lines have significantly elevated MYC mRNA and protein expression. These results were validated using primary patient tumor samples from the neoadjuvant ISPY TRIAL (N= 138 patients) as well as a separate cohort of primary tumor samples for which quantitative protein expression was determined (N= 208 patients). In the ISPY TRIAL an increased expression of the MYC gene signature was associated with worse outcome in patients with substantial residual tumor burden after neoadjuvant chemotherapy (RCB Class II and III). We sought to exploit this increased MYC activity in triple-negative tumors using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. We found that triple-negative breast tumor cells undergo cell death in a MYC-dependent manner following treatment with several CDK inhibitors, including SCH72796 that is in Phase II clinical trials. We find that CDK inhibition effectively induces tumor regression in human tumor xenografts. CDK inhibition in triple-negative breast cells up-regulates the pro-apoptotic BCL2 family member BIM. Our findings support the exploration of CDK inhibitors as treatment for triple-negative breast cancers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S5-4.
Abstract S6-10: Identification of a Novel Tumor Suppressor Network Reveals a Role for Proto-Oncogenic Receptor Tyrosine Kinases in Triple-Negative Breast Cancer
Authors: Sun T , Meerbrey KL , Kessler J , Botero M , Migliaccio I , Nguyen DX , Pavlova NN , Bernardi RJ , Schmitt E , Hilsenbeck SG , Creighton CJ , Shaw CA , Gibbs R , Wheeler D , Osborne CK , Schiff R , Elledge SJ , Westbrook TF.
Published: April 2011

Breast cancer is a collection of diseases with distinct clinical behaviors and underlying genetic causes. Triple-negative breast cancer (TNBC) is a common subtype of breast cancer that confers a particularly poor prognosis and is refractory to current targeted therapies. Unfortunately, the molecular determinants driving this aggressive malignancy are poorly understood. Using an unbiased genetic screen, we have identified a novel tumor suppressor network that governs proliferation and transformation of TNBCs in vitro and in vivo. We define SECT21 as a core component in this network and a commonly inactivated tumor suppressor in TNBC. SECT21 is a potent suppressor of human mammary epithelial cell proliferation and transformation. SECT21 function is frequently compromised in human TNBCs by inactivating mutations, deletion, or loss of protein expression. Mechanistically, SECT21 is a tyrosine phosphatase that suppresses cellular transformation by interacting with and inhibiting several oncogenic receptor tyrosine kinases including HER2, EGFR, and PDGFR. Notably, the tumorigenic and metastatic potential of SECT21-deficient TNBCs is severely impaired by restoring SECT21 function or by inhibiting kinase targets of SECT21, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by SECT21. Collectively, these data identify SECT21 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting tyrosine kinases in TNBC and other cancers based on their profile of tyrosine phosphatase activity.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-10.
Abstract S6-4: Association between Prescription Co-Payment Amount and Compliance with Adjuvant Aromatase Inhibitor Therapy in Women with Early Stage Breast Cancer
Authors: Hershman DL , Neugut AI , Subar M , Wilde ET , Stratton S , Brouse CH , Hillyer G , Grann V.
Published: April 2011

Background: Non-adherence to adjuvant hormonal therapy among women with breast cancer is common, but little is known about how financial factors influence it. We investigated the relationship between prescription co-payment amount and compliance with adjuvant aromatase inhibitors (AI) therapy.

Patients and Methods: Using de-identified, integrated pharmacy and medical claim database at Medco Health Solutions, Inc. women >50 years old on AIs for early breast cancer with at least 2 mail order prescription refills between 1/1/07 and 12/31/08 were identified. All data were pooled prior to the analysis. Variables that were evaluated included medical and demographic information, household income, number of other prescriptions, diagnostic codes, prescription refill dates, provider type and co-payment amounts. Age was classified as <63 or ≥63 to distinguish patients ever covered by Medicare. Copayment amount was categorized as <$30, between $30 and $89.99, and ≥$90. Non-persistence was defined as prescription supply gap of 45 days with no subsequent refill. Non-adherence was defined as a medication possession ratio ≥80% of eligible days. Logistic regressions and Cox proportional hazards modeling were used. Results: Of 8110 women age 50-62 years (mean=59.1), 1721(21.2%) were non-persistent and of those who continued, 863(10.3%) were non-adherent over the 2 year period. Among 14,050 women ≥63 years (mean=74.9), 3476(24.7%) were non-persistent and of those who continued, 1248(8.9%) were non-adherent. Ninety day co-payments ranged from $0 to $893.49. In a multivariate analysis, non-persistence (ever/never) in both age groups was associated with older age, having a primary care physician write the prescription, and higher number of co-prescriptions. Similar results were seen with non-adherence. Compared to a copayment of <$30, a 90 day copayment of $30-$89.99 was associated with time to non-persistence in women ≥63 (HR 1.34, 95%CI 1.24-1.46) but not among women <63, while a copayment ≥$90 was associated with time to non-persistence both in women <63 (HR 1.26, 95%CI 1.09–1.38) and women ≥63 (HR 1.33, 95%CI 1.22–1.46).

Conclusions: We found that a higher prescription co-payment was associated with both early discontinuation and non-adherence to AIs. This relationship was stronger for older women. Because hormone therapy non-compliance is associated with worse survival outcomes, future public policy efforts should be directed towards reducing financial constraints as a means of increasing the use of these life-saving medications.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-4.
Abstract S6-8: Hedgehog Ligand Overexpression Predicts Poor Outcome in Breast Cancer and Is a Potential Therapeutic Target for Metastatic Disease
Authors: O'Toole SA , Machalek D , Shearer R , Millar EKA , Nair R , Martelotto L , McLeod D , Cooper C , Ru Qiu M , Sutherland RL , Watkins DN , Swarbrick A.
Published: April 2011

Background: The Hh signalling pathway plays an important role in a number of malignancies, and accumulating data suggest it contributes significantly to the development and progression of breast cancer. However, there is scant data regarding the clinical significance of its dysregulation in breast cancer and its functional effects in breast cancer models.

Methods: We investigated the clinical significance of the expression of Hh pathway components using immunohistochemistry in a well-characterised cohort of 279 patients with invasive ductal carcinoma (IDC) to determine its prognostic significance. A murine mammary cancer allograft model based on the M6 cell line, derived from the C3/SV40T transgenic mouse was used to determine the effects of Shh overexpression on tumour growth in vitro and in vivo. Finally, the therapeutic potential of Hh blockade using the monoclonal antibody 5E1 was also explored in two mouse mammary carcinoma models; the M6 allograft model and the highly metastatic 4T1 cell line in immunocompetent Balb/C mice.

Results: High Hh ligand expression was observed in 34% of IDC and was associated with increased risk of breast cancer recurrence (HR 1.95, p=0.0004) and breast cancer specific death (HR 2.3, p=0.0002). High Hh expression was also associated with the basal-like subtype (p=0.004). Overexpression of Hh ligand in M6 cells transplanted to fat pads of immunodeficient mice resulted in a 4 fold increase in tumor volume (p= 0.006) and was associated with upregulation of the canonical Hh target genes Gli1 and HHIP. However, Shh promoted peritumoral lymphatic invasion in 4/5 mice compared to only 1/5 in the vector control group and was associated with a significantly shorter time to the development of metastatic disease (p=0.0004). M6 cells overexpressing Hh ligand showed no change in proliferation, self renewal or migration in vitro, suggesting a requirement for stromal interaction in Hh-dependent tumor promotion. Finally, we found that the enhanced tumor growth conferred by Hh ligand overexpression could be blocked by administration of a neutralizing antibody to Hh ligand. Furthermore, using a metastatic mammary carcinoma isograft model (4T1) that endogenously expresses Hh ligand, we demonstrate that Hh blockade resulted in smaller lung metastatic deposits (p=0.045).

Conclusions: We found that high Hh ligand is associated with a poor prognosis in IDC. Overexpression of Hh ligand promotes murine mammary tumor growth, which requires stromal interaction, as well as lymphatic vessel invasion. Finally, we demonstrate that blockade of the Hh ligand is a potential therapy in metastatic breast carcinoma.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-8.
FGFR3 Is Overexpressed Waldenström Macroglobulinemia and Its Inhibition by Dovitinib Induces Apoptosis and Overcomes Stroma-Induced Proliferation
Authors: Azab Abdel Kareem , Azab Feda , Quang Phong , Maiso Patricia , Sacco Antonio , Ngo Hai T. , Liu Yang , Zhang Yong , Morgan Brittany L. , Roccaro Aldo M. , Ghobrial Irene M.
Published: April 2011

Purpose: There is no standard of therapy for the treatment of Waldenström macroglobulinemia (WM), therefore there is a need for the development of new agents. Fibroblast growth factor receptor 3 (FGFR3) was shown to play a major role in several types in cancer. Dovitinib, an inhibitor of FGFR3, was effective in hematologic malignancies. In this study, we tested FGFR3 as a therapeutic target in WM and tested the effect of dovitinib on cell proliferation and apoptosis of WM cells in the context of BM microenvironment.

Methods: The expression of FGFR3 in WM cells was tested using immunofluorescence and flow cytometry. Cell signaling in response to stimulation with FGF3 and stromal cells, and its inhibition by dovitinib was performed using immunoblotting. Cell survival and cell proliferation were assessed by MTT and BrdU assays. Apoptosis was measured by detection of APO-2.7 and cleavage of caspase-3 using flow cytometry. Cell cycle was performed by PI staining of cells and flow cytometry. The combinatory effect of dovitinib with other drugs was analyzed using Calcusyn software. The effect of dovitinib was tested in vivo.

Results: FGFR3 was overexpressed in WM cells and its activation induced cell proliferation. Inhibition of FGFR3 with dovitinib decreased cell survival, increased apoptosis, and induced cell cycle arrest. Inhibition of FGFR3 by dovitinib reduced the interaction of WM to bone marrow components, and reversed its proliferative effect. Dovitinib had an additive effect with other drugs. Moreover, dovitinib reduced WM tumor progression in vivo.

Conclusion: We report that FGFR3 is a novel therapeutic target in WM, and suggest dovitinib for future clinical trial the treatment of patients with WM. Clin Cancer Res; 17(13); 4389–99. ©2011 AACR.