bluuebunny/crossref_metadata_2025 huggingface dataset:
Did survival of patients with distant metastasis from breast cancer improve during the last three decades? A cohort study on 4071 breast cancers.
Authors: Delozier T , Switsers O , Ollivier J , Levy C , Rivière A , Allouache D
Published: December 2010

Abstract #3129

Introduction: During the last three decades we observed a dramatic improvement in disease free and overall survival in early breast cancer. The improvement of survival of patients who underwent distant metastases is not obvious.  The objective of the study was to determine whether the survival of women with distant recurrent breast cancer has improved from 1973 to 2002.  Method: We analyzed survival of 4071 women who developed distant metastasis from breast cancer between January 1973 and December 2002 whatever the primary tumor status and initial treatment were. Patients were divided into five groups based on year of breast cancer distant recurrence.  Results: In the unadjusted analysis there was a slight but significant improvement in survival across the five groups (p<0.0001), leading to a median survival time of 11.0, 13.9, 17.9, 16.2, 17.3 and 19.8 months respectively and a two-year survival probability of 27.2, 32.3, 39.6, 37.6, 38.7 and 41.0% respectively. In a multivariate analysis including other prognostic factors for metastatic breast carcinoma (age, tumor size, node involvement, tumor grade, estradiol receptors status, site of metastasis and delay from primary treatment), year of recurrence remain a prognostic factor (p=0,001).  Survival improvement was more obvious for women with bone metastasis and for women under 70 years old when primary treatment did not include adjuvant chemotherapy.  Conclusion: These results suggest that survival of women with distant recurrent breast cancer improved during the last three decades. Nevertheless this improvement is moderate and the long term survival probability is still weak.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3129.
A phase II study of ixabepilone plus trastuzumab for metastatic HER2-positive breast cancer.
Authors: Tolaney SM , Najita J , Chen W , Savoie J , Fornier M , Krop IE , Winer EP , Bunnell C
Published: December 2010

Abstract #3137

Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.  Methods: This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers.  Results: 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented.  Conclusion: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.
Lapatinib can restore capecitabine sensitivity in HER2-positive breast cancer.
Authors: Cha Y , Kim H , Han S , Oh D , Kim J , Im S , Bang Y , Kim T
Published: December 2010

Abstract #3157

Background: Lapatinib in combination with capecitabine is an effective treatment option in HER2-positive metastatic breast cancer (MBC) that has progressed after trastuzumab-based therapy. However, the efficacy of lapaptinib plus capecitabine in capacitabine resistant MBC patients and mechanism of sensitivity in these patients is unclear.  Methods: In the preclinical part of the study, the effect of lapatinib on 5-FU sensitivity was investigated in a HER2 amplified breast cancer cell line (SKBr3). In the clinical part, MBC patients who progressed after treatments with trastuzumab, anthracycline, and taxane were enrolled in an open-label expanded-access study of lapatinib plus capecitabine (GlaxoSmithKline, USA) at Seoul National University Hospital from Mar 2007 to Apr 2008. Patients received lapatinib (1,250mg/day, 1-21) and capecitabine (2,000mg/m2, D1-14) combination treatment every 3weeks. The clinical data were prospectively collected.  Results: In SKBr3 cell line, genes related to 5-FU sensitivity [TS, thymidine kinase 1(TK1), dihydrofolate reductase (DHFR), and ribonucleotide reductase M2 (RRM2)] were downregulated after lapatinib treatment. These genes were more significantly reduced after lapatinib-treatment compared with gefitinib or trastuzumab. In addition, TS reporter gene expression was enhanced by EGFR/HER2. Nuclear translocation of EGFR/HER2 induced by EGF and its association with TS promoter was effectively abolished by lapatinib. In the clinical study, a total of 37 female patients with HER2-positive MBC were analyzed. Sixteen (43%) patients had previously been treated with capecitabine. Overall response rate (RR) was 27.0% (95% CI 12.7-41.3), and disease control rate (DCR) was 83.8% (95% CI 71.9-95.7). During the median follow-up duration of 9.1 months, median progression-free survival (PFS) was 5.6 months (95% CI 4.0-7.2), and median overall survival has not been reached yet. There was no significant difference in RR/DCR and PFS according to prior capecitabine use. Prior capecitabine treatment had been discontinued due to disease progression during treatment in 13 patients. Among these patients with resistance to capecitabine, lapatinib and capecitabine resulted in DCR/PFS comparable to that of patients without exposure to capecitabine. Biomarker analysis of tissue specimen is currently underway and will be presented at the meeting.    Conclusion: Lapatinib plus capecitabine demonstrated clinical activity in capecitabine pretreated MBC. Our data suggests that lapatinib may resensitize capecitabine resistant tumors to capecitabine by downregulation of nuclear EGFR/HER2 and TS.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3157.
Cardiac toxicity and adjuvant trastuzumab for breast cancer – the Cancer Centre of Southeastern Ontario experience.
Authors: Flemming JA , Hopman W , Madarnas Y
Published: December 2010

Abstract #3158

Background: In May 2005 several large randomized trials reported a significant improvement in DFS following the addition of trastuzumab (T) to adjuvant chemotherapy (CT) in early stage breast cancer (BC) such that in the summer of 2005 adjuvant T became standard of care for patients (pts) whose tumors over-expressed her2. Cardiotoxicity had been reported as the main toxicity suffered by pts exposed to T. As the generalizability of clinical trial results to the 'real world' is under increasing scrutiny from the oncology community, we undertook this study to identify and follow the population of interest and to characterize cardiac toxicity related to adjuvant T as practice changed.  Methods: We conducted a retrospective review of electronic and paper records of all pts prescribed adjuvant T for early stage BC at the Cancer Centre of Southeastern Ontario from June 2005 through January 2007; collecting demographic, disease-related, and treatment-related variables, along with serial left ventricular ejection fraction (LVEF) measurements for each pt.  Results: 54 pts prescribed adjuvant T were identified in this time period, nearly half of which were still on T at the time of this analysis. Mean age was 54.4 ± 9.5 years, 38.9% had N0 disease, and 40.7% had left sided tumors, with 42.6% being ER+ and 50% being PR+. Most pts received anthracycline based CT (53.7%) and 39% received an anthracycline/taxane combination. T was concurrently with CT in 14.8% of pts, concurrently with radiotherapy in 33.3% and sequentially in the remainder. T was initiated at a mean of 91.2 days from completion of chemotherapy (range 19-365). Our local protocol mandated LVEF assessments at baseline pre CT, upon completion of CT and/or prior to initiation of T for all pts, and while on T all pts underwent LVEF assessments at 12, 24, 36, 48 and 52 weeks, and in response to any symptoms suggesting cardiac dysfunction. Mean LVEF pre CT and post CT was 64% and 62% respectively. We saw no change in LVEF post CT and pre T. We noted a significant decline in LVEF after 12 weeks on T, from 60.5 ± 6.2% to 56.5 ± 9.5% respectively (p = 0.003), with LVEF values remaining stable thereafter. However, at the time of this analysis only approximately half the pts had completed the full year of therapy. Twelve pts (22.2%) interrupted their T therapy due to a drop in LVEF of >10%, only one pt experienced symptomatic cardiotoxicity requiring treatment. Of these twelve, only two pts restarted T at a later date. Follow-up of those patients still on trastuzumab is ongoing.  Discussion: Adjuvant trastuzumab in general clinical practice is associated with significant decreases in LVEF that are associated with premature discontinuation of therapy. A better understanding of factors associated with LVEF decline and the trends in LVEF over time may allow for targeted interventions for pts at risk.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3158.
Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer.
Authors: Burstein HJ , Sun Y , Tan AR , Dirix L , Vermette JJ , Powell C , Zacharchuk C , Badwe RA
Published: December 2010

Abstract #37

Background: Neratinib (HKI-272) irreversibly inhibits the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity in patients (pts) with solid tumors, including 8 of 25 evaluable pts with erbB2-positive advanced breast cancer. In this open-label, 2-arm phase 2 study, pts with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib.  Methods: ErbB2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Pts were assigned to arm A if they had prior treatment with trastuzumab and to arm B if they had no prior treatment with trastuzumab or other erbB2-targeted drug. All pts received oral doses of 240 mg of neratinib daily. The primary endpoint was progression-free (PFS) survival rate at 16 weeks (wks).  Results: Enrollment of 136 pts (arm A: 66 pts; arm B: 70 pts; median age 50 years [range 31-83 years]) was completed in November 2007. Common neratinib-related adverse events (AEs), any grade, were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Diarrhea was the only ≥grade 3 AE that occurred in ≥5% of pts, 26/136 (19%) total pts, 27% in arm A and 11% in arm B. Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea. The main reasons for discontinuation of the study were disease progression (arm A: 74%, arm B: 43%), and AEs (arm A: 8%, arm B: 4%).  124 pts (arm A: 61 pts, arm B: 63 pts) were evaluable for efficacy based on independent assessment and 131 pts (arm A: 65 pts, arm B: 66 pts) were evaluable based on investigator assessment. The objective response rates (complete or partial response) were 26% (95% CI 16%, 39%) in arm A, 51% (95% CI: 38%, 64%) in arm B for independent assessment and 34% (95% CI: 23%, 47%) in arm A, 62% (95% CI: 49%, 74%) in arm B for investigator assessment. The 16-wk PFS rates were 61% in arm A, 75% in arm B (independent); 57% in arm A, and 78% in arm B (investigator). The median PFS for independent [and investigator assessment] was 23 [22] wks in arm A and 40 [35] wks in arm B.  Discussion: Neratinib demonstrates robust antitumor activity in pts with erbB2-positive advanced breast cancer, with objective response rates of 26% in pts who had prior treatment with trastuzumab and 51% in pts who had no prior treatment with trastuzumab. Additional updated efficacy and safety data will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 37.
Identification of new breast cancer candidate genes associated with stromal invasion.
Authors: Liao S , Gaile DP , Shepherd L , Desouki MM , Geradts J
Published: December 2010

Abstract #4036

Background: We recently reported our results of a study identifying a number of DNA copy number changes that differentiated low grade ductal carcinoma in situ (DCIS) lesions with and without associated stromal invasion. We now describe a series of validation experiments that support the role of four genes in early breast cancer progression, most of which were not previously implicated in mammary neoplasia.  Materials and Methods: DNA was extracted from microdissected paraffin sections of formalin fixed low grade DCIS lesions with an invasive component (n=25), as well as morphologically similar DCIS lesions without associated invasion within at least 5 years (n=20). The DNA was used for comparative PCR, with GAPDH as the reference gene. Specific primers were designed for fourteen candiate genes. Amplicon sizes ranged from 80 to 90 base pairs. Using log2 ratio cutoffs of +1.0 and -0.5, respectively, the frequency of copy number gains and losses was determined for each candidate gene. Additional validation studies employed genomic DNA samples from an independent cohort of 35 microdissected DCIS lesions with (n=17) and without (n=18) an associated invasive component.  Results: Our previous whole genome profiling study using high density BAC arrays revealed that DNA copy number changes on 1q, 3p, 5q, 6p, 9p, 10q, 11q, 12q, 16p, 16q, 18q, 20q, and 22q may occur at different rates in low grade DCIS lesions with and without associated stromal invasion. From the differentially amplified or deleted chromosomal sites, thus far we have selected fourteen candidate genes for validation by comparative PCR, utilizing aliquots of the same DNA samples that had previously been used for array CGH analysis. Four genes were confirmed to have differential copy number changes. NCOR2 (on 12q24.31), DYNLRB2 (on 16q23.2), CELSR1 and UPK3A (both on 22q13.31) were more frequently amplified in DCIS lesions that had no invasive component. Moreover, NCOR2 and DYNLRB2 showed more frequent copy number losses in DCIS lesions that had progressed to invasive carcinoma. For NCOR2, these observations held true in an independent cohort of microdissected low grade DCIS cases. The other ten candidate genes revealed significant frequencies of copy number changes that were not differentially distributed, however. TEME9, CALN1, and CENTA1 were amplified in 30-40% of all cases. IRF8, THAP7, and FIGNL1 were deleted in 20-50% of all cases. FBXO31, CDH13, IKZF1, and MAPK9 revealed both gains and losses in >20% of all cases.  Discussion: Our validation experiments have provided additional evidence for the role of several novel genes in early breast cancer progression. Four of the candidate genes we assayed so far may function as invasion suppressor genes. Ten additional genes showed significant copy number changes but did not discriminate DCIS lesions with and without the propensity to invade the stroma.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4036.
Biomarker analysis by tissue microarray technology of Bik, Bcl-2, Bax, ER-α, ER-β, Her2/neu, PCNA, P53, pRB proteins and apoptotic index (by TUNEL) in breast cancer Mexican biopsies.
Authors: Garcia-Hernandez N , Arenas D , Murillo-Ortiz B , Meneses A , Muñoz D , Ruiz-Garcia E , Astudillo-de la Vega H
Published: December 2010

Abstract #4043

Background:   The development and progression of epithelial cancers are the results of changes in many genetic networks. Through massive analysis techniques various prognostic factors have been studied to determine proteins implicated in cancer. A new technology used is tissue microarray (TMAs), which allows the assessment of several patients at different stages in a single slide.  Methods:  TMA blocks with up to 128 cylinders were made by using 1.5-mm diameter tissue cores from each paraffin block. In a series of 70 formalin-fixed carcinomas, we analyzed the immuno-expression of Bik, Bcl-2, Bax, ER-α, ER-β, Her2, PCNA, P53 and RB proteins. For apoptosis detection the TUNEL technique was used. Expression profiles for these tumors were generated with an unsupervised clustering and a T Test analysis.  Results:  We developed TMAs with samples from Mexican women with breast cancer at different stages (type I, II and III) and compared these with those of non affected breast tissue of the same women's samples. Through a hierarchical cluster we found three subgroups of tumors according to protein expression behavior. The apoptotic process was found in low grade 4.28%; moderate grade 90% and high grade 5.71% of samples. Statistical analysis revealed that Bax gene (p=0.000) expression was significantly increased in samples stage I and underexpressed in samples stage IIIA. The Bcl-2 gene was under-expressed in the majority of samples of the stage II. Even when the Bik gene was detected the protein level was over-expressed in 44.29% of the cases with noa significant correlation with apoptosis (TUNEL) (p=0.006). The samples where there were more alterations of the studied proteins were understood in the stages IIA (T2N0M0) and IIB (T2N1M0).    Conclusions:  The analysis of specimens of several patients in different stages of the disease turns out to be useful to establish a better diagnosis and prognosis. Differential regulation of these genes, especially Bik and Bax, may contribute to the biological nature of a clinically more aggressive and highly proliferative breast cancers.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4043.
SIRT7 expression and epigenetic status determine variability in telomere length in breast cancer.
Authors: Zino S , Moran CP , McGlynn LM , George W , Payne AP , Shiels PG
Published: December 2010

Abstract #4052

Background: As cancer is a disease of ageing, factors involved in biological ageing may be informative in investigating the underlying mechanisms of cancer pathogenesis. How biological age is affected by epigenetic changes remains to be fully determined. This is pertinent to cancer pathogenesis, as epigenetic changes can increase the risk of neoplasia. We have investigated the biological age of breast tumours, using telomere length and the expression of sirtuin 7, a gene involved in the regulation of ribosome biosynthesis and previously demonstrated as potentially prognostic in breast cancer. We have evaluated these for association with epigenetic status.  Materials and Methods: Telomere lengths and Sirtuin 7 (SIRT7) expression were determined using Q-PCR. Epigenetic status was determined using a Methylamp Global DNA methylation kit. Statistical analysis was performed using SPSS v15.  Results: Chronological age was negatively associated with telomere length (p=0.013) and positively associated with methylation levels (p=0.007). Furthermore, telomere length showed a negative association with global methylation levels (p=0.002). Individuals with shorter telomeres were older and demonstrated higher levels of global DNA methylation. SIRT7 expression was positively associated with telomere length (p=0.01), but showed no association with methylation levels. Linear regression analysis indicated that SIRT7 expression accounted for 52.2% of the observed variability in telomere length (p=0.001) and methlyation for 33.4% (p<0.001). Multiple linear regression analysis indicated that methylation status and SIRT7 expression combined accounted for 69.4% of the observed variability in telomere length. Chronological age was not a significant contributor in either analysis.  Discussion: Cells with critically short telomeres present a high risk of becoming neoplastic, as they are biologically aged. This study has demonstrated that both SIRT7 expression and global methylation levels significantly influence telomere attrition in breast cancer. This is consistent with a scenario whereby the rate of biological ageing in breast tumours is influenced by telomere mediated epigenetic changes and mechanistically by cellular proliferation requirements. The latter is manifest through SIRT7 regulated ribosome biogenesis. These findings support the use of SIRT7 as a potential prognostic tool and therapeutic target in breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4052.
The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of the focal adhesion kinase and p130Cas in breast cancer cells.
Authors: Zhao Y , Min C , Vora S , Trackman PC , Sonenshein GE , Kirsch KH
Published: December 2010

Abstract #4073

The lysyl oxidase (LOX) gene encodes an enzyme (LOX) critical for extracellular matrix maturation. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. In particular, the pro-peptide domain (LOX-PP) of the secreted precursor protein (Pro-LOX) was found to inhibit the transformed phenotype of breast, lung and pancreatic cancer cells. LOX-PP expression in these carcinoma cells reverted Her-2/neu- and Ras-mediated epithelial to mesenchymal transition (EMT), leading to increased expression of E-cadherin and γ-catenin, and reduced levels of Snail, vimentin and/or BCL2, as well as invasion through Matrigel. Furthermore, LOX-PP expression reduced tumor formation of Her-2/neu driven breast cancer cells in a xenograft model. However, the mechanism of action remains to be determined. Here the ability of LOX-PP to attenuate the integrin signaling pathway in NF639 breast cancer cells driven by Her-2/neu, which signals via Ras, was tested. Ectopic Pro-LOX and LOX-PP expression inhibited fibronectin-stimulated protein tyrosine phosphorylation. Importantly, phosphorylation of the focal adhesion kinase (FAK) on Tyr397 and Tyr576, and the activation of its downstream target p130Cas were substantially reduced. Furthermore, these changes were also reflected by a reduced amount of endogenous p130Cas in the Triton X-100 insoluble protein fraction, and attenuation of fibronectin-activated haptotaxis. Interestingly, expression of mature LOX enzyme enhanced fibronectin-stimulated integrin signaling. Of note, treatment with recombinant LOX-PP reduced haptotaxis of NF639 and human MDA-MB-231 and Hs578T breast cancer cells. Thus, the tumor suppressor function of LOX-PP is likely mediated, in part, by blocking integrin signaling and fibronectin-stimulated cell migration.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4073.
Assessment of breast cancer risk prediction models in a high-risk population.
Authors: Chun J , Schnabel F , Ogunyemi O
Published: December 2010

Abstract #4074

Background: A variety of risk assessment models have been developed to quantify a woman's risk for developing breast cancer. Although the Gail model (GM) is the most widely utilized model, there are limitations. The Tyrer-Cuzick model (TCM), which has been validated in the United Kingdom (UK), addresses these limitations but its performance in other populations is unclear. The purpose of this study was to evaluate the predictive ability of the TCM in a cohort of high-risk women from the New York metropolitan area and compare the results to the GM.  Methods: The Women At Risk (WAR) Registry provided the study population. Due to the age limitation of the Gail model, we excluded women who were under 35 and over 80 years of age. Calculation of lifetime Gail scores included the following: age, race, age at first menses, age at first live birth, number of first degree relatives with breast cancer, number of previous breast biopsies, and atypical hyperplasia. These variables were also included in the lifetime Tyrer-Cuzick scores as well as information on menopausal status, use of hormone replacement therapy, LCIS, and age at diagnosis for relatives with ovarian and breast cancer. The Receiver Operating Characteristic (ROC) and estimated area under the ROC curve (AUC) with 95% confidence intervals (CI) were used to assess prediction accuracy of both models.  Results: Out of a total study population of 1523 women, 82 (5%) developed breast cancer during a median follow-up of 56 months. The median age of women without breast cancer was 49 years, and the median age of women who developed breast cancer was 54 years. The AUC and 95% CI for the Gail model was 0.547 (0.479 to 0.615) and 0.501 (0.433 to 0.569) for the Tyrer-Cuzick model. Our results indicate poor discriminatory accuracy for both models, which performed no better than pure chance (0.5).    Discussion: Quantitative breast cancer risk assessment models are critically important in developing effective risk management strategies. Although the TCM addresses some limitations of the GM, it is unclear how well it performs in populations outside the UK due to the wide variation in international breast cancer rates. In addition, the TCM excludes more recently identified risk factors such as breast density. Bayesian techniques may ultimately lead to a better risk assessment tool as they allow continual modification of the model as new risk factors are identified. Accurate breast cancer risk prediction is a complex undertaking and further studies are warranted in order to achieve truly comprehensive and widely applicable models.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4074.
17β-estradiol levels during an entire menstrual cycle in response to adult stature and insulin, of possible importance for breast cancer risk. The EBBA-I study.
Authors: Espetvedt S , Emaus A , Tretli S , Jasienska G , Ellison P , Furberg A , Wist E , Thune I
Published: December 2010

Abstract #4078

Background: The normal breast cells develop into malignant cells as a result of a complex interplay between genetic, environmental, nutritional and hormonal factors. Attained adult stature and insulin levels, risk factors for breast cancer, may also vary in response to the same factors. Thus, we hypothesize that 17β-estradiol, a key factor in the carcinogenesis of the breast, may vary in response to adult height in combination with insulin levels of possible importance of breast cancer risk.  Methods: Among 204 healthy women, aged 25-35 years who participated in the Norwegian EBBA-I study, 17β-estradiol concentrations were measured in daily saliva samples throughout one entire menstrual cycle using radioimmunoassay (RIA). Attained height (cm) was measured, and serum concentrations of insulin were determined in fasting blood samples. The associations between adult height, insulin and 17β-estradiol levels throughout a menstrual cycle were studied using multivariate linear regression analyses and linear mixed models for repeated measures. Adjustments for potential confounding factors were performed.  Results: A 37.2 % increase in 17β-estradiol levels was observed during the entire menstrual cycle among women with an adult height ≥170 cm (upper tertile) and insulin levels ≥ 90 pmol/L (upper tertile) compared to women with the same attained adult height, and insulin levels < 90pmol/L. The association was even more pronounced when we looked into those women with attained adult height ≥170 cm (upper tertile) and serum insulin ≥ 101 pmol/L (upper quartile) (Fig. 1). Adjustments for potential confounding factors were performed.    Conclusion: Our findings support that premenopausal levels of 17β-estradiol vary in response to adult height and insulin levels, suggesting that women who become taller are put at risk for higher estradiol levels throughout the entire menstrual cycle when their insulin levels rise, of possible importance for breast cancer risk.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4078.
Final results of the RAPP-01 phase III trial comparing doxorubicin and docetaxel with doxorubicin and cyclophosphamide in the adjuvant treatment of high-risk node negative and limited node positive (≤3) breast cancer patients.
Authors: Brain EG , Debled M , Eymard J , Bachelot T , Extra J , Serin D , Combe M , Fourme E ,   Group of RAPP-01 Investigators
Published: December 2010

Abstract #4101

Background  Taxanes have been approved in the adjuvant setting for the treatment of node positive (pN+) breast cancer (BC) patients (pts), given either sequentially or in combination with anthracyclines. Controversies remain regarding their role in high-risk node negative (pN0) disease.  Methods  In 1999, we initiated a randomised phase III trial comparing 4 cycles of adjuvant doxorubicin + docetaxel (AT, 50/75/mg/m²) with 4 cycles of standard doxorubicin + cyclophosphamide (AC, 60/600/mg/m²) in a mixed population of high-risk pN0 and limited pN+ (≤3) early BC pts. Chemotherapy was delivered postoperatively q3w without prophylactic G-CSF, followed by radiation therapy according to standard guidelines and endocrine treatment for 5 years in pts with ER±PgR-positive tumours. This trial was closed prematurely for toxicity in 2003 and we have reported the safety data (JAMA 293:2367, 2005). We now report on time to recurrence (TTR, primary endpoint defined as locoregional relapse, controlateral BC or distant metastasis, which ever occurs first) as well as the effect of treatment by stratification factors [pN and Ki67 (<25% vs ≥25%)].  Results  Of 700 pts planned, 627 were enrolled between 6/1999 and 1/2003. Baseline characteristics of all pts were well-matched, with 43% of pN0 and 44% of Ki67 ≥25%. At a median follow-up of 64 months, there was no statistically significant difference in TTR between AT and AC. In the AT group, there were 28 TTR events (5-year TTR 91%, 95%CI: [88-94%]) and 16 deaths all causes (2 toxic deaths); the AC group had 31 TTR events (5-year TTR 90.9%, 95%CI: [88-94%]) and 18 deaths all causes.    Conclusions  With 5-year median follow-up, there is no difference in TTR between pts treated with AT or standard AC in adjuvant setting. Specific nodal or Ki67 status do not confer any additional benefit from either regimen. Both regimen provide an excellent 5-year TTR rate (>90%). Multivariate analysis including all prognostic covariates will be performed and presented at the meeting. Given the high risk of life-threatening complications already reported, AT is not manageable without preventive strategies (e.g. G-CSF) and cannot be considered as a standard combination for intermediate risk early BC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4101.
Phase III two by two factorial comparison of doxorubicin and cyclophosphamide followed by a taxan vs. a taxan alone, and paclitaxel vs. docetaxel in operable node positive breast cancer – results of the first interim analysis of NSASBC02 trial.
Authors: Watanabe T , Kuranami M , Inoue K , Masuda N , Aogi K , Oono S , Iwata H , Mukai H , Tanaka S , Yamaguchi T , Ohashi Y
Published: December 2010

Abstract #4103

Background: Evidence suggests that anthracycline-containing regimens can be excluded in some patients(pts) with operable breast cancer. It is also suggested that docetaxel (D) is more effective than paclitaxel (P) in metastatic breast cancer (BC) pts.  Methods: Eligibility included axillary lymph node positive BC age less than 70 years old. Pts were randomized to receive either AC(doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every(q) 3 weeks(wks) x 4 followed by P 175 mg/m2 q3 wks x 4 (ACP), same AC followed by D 75 mg/m2 q3 wks x 4(ACD), P 175 mg/m2 q3 wks x 8 (PTX) or D 75 mg/m2 q3 wks x 8(DTX). Comparison included taxane (ACP+PTX vs. ACD+DTX) and with AC or without AC (ACP+ACD vs. PTX+DTX). The primary endpoint was disease free survival (DFS) and the secondary endpoints included overall survival, adverse events(AE) and quality of life (QOL). The trial was powered to prove the non-inferiority of regimens without AC to those with AC(threshold hazard ratio 1.321) in terms of DFS.  Results: A total of 1,060 eligible pts were accrued from 84 centers between Dec. 2000 and Mar.2006. 270 DFS events and 106 deaths after a median follow-up of 46.5 months were observed. The hazard ratio (HR) of DFS between ACD+DTX and ACP+PTX was 0.81(95% Confidence Interval (CI); 0.64-1.03) (p=0.08). The HR of DFS between PTX+DTX and ACP+ACD was 1.26 (95% CI; 0.99-1.60) ( p=0.67) in all eligible pts but was 1.85 (95% CI; 1.11-3.07)(p=0.017) in pts with HER2 overexpressing BC and 1.11(95% CI; 0.85-1.46)( p=0.44) in pts with HER2 non-overexpressing BC. AEs of grade 3 or 4 were observed in the lowest incidence in PTX arm and edema was observed in 11% of pts in DTX arm(p=0.01), neutropenic fever was more frequent in D cotaining arms(Table1). Conclusions: DFS was better in the arms containing D than in the arnms with P. AC improved DFS in the subset of pts with HER2 overexpressing BC but not in non-selected population. Higher incidence of severe AEs was observed in the arms containing D than in arms with P.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4103.
Safety of bevacizumab (BV) plus docetaxel (D) in patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC) who developed brain metastases during the AVADO phase III study.
Authors: Dirix LY , Romieu G , Provencher L , Grimes D , de Souza Viana L , Paterson A , Mauriac L , Kirsch A , Pernas S , Miles DW
Published: December 2010

Abstract #4116

Background: BV (Avastin®) is a monoclonal antibody specific to VEGF. The randomised, double-blind AVADO study has demonstrated that two different BV doses combined with D significantly improved progression-free survival in pts with LR or mBC compared with D + placebo (PL); unstratified hazard ratio (HR) up to 0.72, stratified HR up to 0.61 censored for non-protocol therapy. BV combined with D did not result in increased risk of GI perforations, thromboembolic or bleeding events. Patients with CNS metastases are currently excluded from clinical trials with BV due to a potential risk of haemorrhage. This retrospective analysis investigated the adverse events (AEs) reported in pts who developed brain metastases while participating in the AVADO trial.  Methods: The AVADO study compared D 100mg/m2 plus PL with D plus BV at either 7.5 or 15mg/kg in 736 pts with HER2-negative inoperable LR or mBC; no chemotherapy 6 months prior to randomisation (≥12 months if taxane-based); ECOG PS 0–1; adequate LVEF, and no CNS metastases at study entry. D was administered q3w for up to 9 cycles. BV/PL was administered q3w until disease progression or unacceptable toxicity.  Results: Of the 730 pts in the safety population, a total of 24 pts developed brain metastases at some point during the AVADO trial. There was no difference in number of pts who developed brain metastases between trial arms. The mean time to development of brain metastases was 172 days with PL, 197 days with BV 7.5mg/kg and 242 days with BV 15mg/kg. One patient receiving BV 15mg/kg was diagnosed with brain metastases on Day 1 and excluded from the study. No CNS bleeding AEs were reported for pts with brain metastases and other grade 3–5 AEs in these pts occurred at a similar frequency in all trial arms.    Conclusions: In concordance with the overall toxicity assessment, treatment with BV did not appear to be associated with CNS haemorrhage in pts with brain metastases. Frequency of grade 3–5 AEs was not increased in pts with brain metastases treated with BV compared with those treated with PL. Analysis of a larger dataset may provide further information on the safety of BV therapy in pts with brain metastases.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4116.
Phase 1b study of motesanib diphosphate (AMG 706) in combination with paclitaxel or docetaxel for the treatment of locally recurrent, unresectable or metastatic breast cancer.
Authors: Kaufman PA , de Boer R , White S , Mainwaring P , Koczwara B , Drury S , Ye Y , Sun Y , Sikorski R , Kotasek D
Published: December 2010

Abstract #4117

Background: Motesanib is a novel oral angiogenesis inhibitor designed to selectively target the tyrosine kinase activity of VEGF 1, 2 and 3; PDGF and Kit receptors. Here we report safety, preliminary efficacy and pharmacokinetics (PK) from an ongoing phase 1b dose-finding study of motesanib plus either paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer.  Methods: Eligible pts with ECOG 0 or 1 and ≤1 prior chemotherapy regimen for metastatic breast cancer received (until toxicity or disease progression) escalating doses of motesanib (50 or 125mg) QD orally continuously from day 3 of cycle 1 plus either P (Arm A) at 90mg/m2 on days 1, 8 and 15 of each 28-day cycle; or D (Arm B) at either 100mg/m2 on day 1 of every 21-day cycle or at 75mg/m2 with motesanib maximum tolerated dose (125mg QD). Objective response (OR) per RECIST was assessed every 8 (Arm A) or 6 wks (Arm B).  Results: To date, 33 pts have received ≥1 dose of motesanib: Arm A, n=10; Arm B, n=23. Median age is 51 (range, 28-66) years. There were 5 DLTs (all grade 3) in 4 pts: abnormal liver function tests and deep vein thrombosis (Arm A, 125mg QD), fatigue (Arm A, 125mg QD), gallbladder enlargement (Arm B, 125mg QD+75mg/m2 D) and migraine (Arm B, 125mg QD). 28 pts (85%) had motesanib-related AEs; the most common were (worst grade): diarrhea, Arm A/B 60%/61% (grade 3, 0%/13%); fatigue, 30%/26% (grade 3, 10%/4%); hypertension, 20%/22% (grade 3, 10%/4%); and nausea, 10%/26% (no grade 3). Treatment-related AEs of interest in Arm A/B included epistaxis (10%/18%; all worst grade 1) and deep vein thrombosis (10%/0%; all worst grade 3). There were no grade 4 or 5 related AEs. Two deaths on study occurred (Arm B; 50 and 125mg QD n=1 each); both were not considered to be motesanib related. Motesanib PK parameters were generally within the range previously described for single-agent motesanib. PK profiles of P and D showed high interpatient variability, with AUC higher in some pts after motesanib coadministration. In pts with measurable disease at baseline (Arms A&B, n=7&18), best OR at time of last data cut-off was: confirmed PR in Arm A n=2 (29%), in Arm B n=5 (28%); SD in Arm A n=2 (29%), in Arm B n=9 (50%); durable SD ≥24 wks in Arm A n=0, in Arm B n=3 (17%). Median (range) duration of response currently is 169 (58-169) days in Arm A and 198 (96-337+) days in Arm B.  Conclusions: Motesanib combined with P or D appears to be tolerable with evidence of antitumor activity in pts with advanced breast cancer. No marked effect on motesanib PK has been noted with coadministration of either P or D. Updated safety and efficacy data, including PFS, will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4117.
Fluvastatin has biologic effects on stage 0 and 1 breast cancer.
Authors: Garwood ER , Kumar AS , Baehner F , Garber JE , Troyan S , Olopade OI , Moore D , Au A , Flowers C , Campbell M , Hylton N , Esserman LJ , Rush-Port E
Published: December 2010

Abstract #4122

Introduction: Statins are safe, reduce cardiovascular risk, and impact pathways critical to cancer progression. We and others have shown lipophilic statins cause apoptosis and growth suppression in vitro and in vivo, and though epidemiologic data are mixed, statin effect appears most evident in estrogen receptor (ER) negative or grade 3 disease. To look for a direct biologic effect of lipophilic statins, we conducted a perioperative pilot window trial in women with breast cancer (BC).  Methods: 40 subjects with stage 0,1 BC were randomized to high dose (80mg/day) or low dose (20mg/day) fluvastatin for 3-6 weeks prior to surgery. Paired tissue (core biopsy and surgical specimen), peripheral blood and MRI were obtained. Primary endpoint was Ki-67 (proliferation) change. Secondary endpoints included cleaved caspase-3 (CC3, apoptosis), longest diameter (LD) by MRI, and C-reactive protein (CRP) change. Subgroup analyses was planned by grade (3 vs. 1,2), statin dose; and ER status. Immunohistochemistry (IHC) on paraffin tissue used standard streptavidin biotin methods. A single breast pathologist reviewed all slides; a single radiologist read all MRIs, both blinded to timepoint.  Results: Median serum cholesterol decreased by 16% (-23% and -12% for high and low dose, respectively p=0.012), indicating drug effect and compliance. 29 patients had sufficient tumor for paired IHC, 14 and 15 were grade 3 and 1,2, and 10 and 19 were ER - and +, respectively. In grade 3 (73% of which were ER-) vs. 1,2 tumors, there was a significant decrease in Ki-67, -7.2% (interquartile range (IQR) -13.4%, 0% ) vs. -0.3% (IQR -3%, .8%), respectively, p=0.04. CC3 (apoptosis) increased, 60% vs. 13% for grade 3 vs. 1,2 tumors, respectively, p=0.015. ER- and ER+ cases had a similar reduction in Ki67 with a median drop of 2% (IQR -13.4%, 1%) and 1.2% (IQR -6.6%,0.8%), respectively, p=0.56. While CC3 was increased in ER- vs. + (55% vs. 29%), the difference was not statistically significant. There was no dose dependent effect on Ki-67or CC3.There was no evidence of Ki67 or CC3 change when all grades were analyzed together (median drop 1.2%) and no change in CRP. Of 14 subjects with paired MRIs, 4 grade 3 cases showed a significant decrease in LD, marked ductal dilatation and increased necrosis.with statin exposure.  Conclusions: A lipophilic statin, fluvastatin, reduced cholesterol and had measurable biologic changes (reduced proliferation, size and increased apoptosis) in stage 0,1 BC after only 3-6 weeks of exposure, specifically in the grade 3 subset. Results support the study of statins for chemoprevention for women at risk for or with stage 0 grade 3 BC, where new agents are needed.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4122.
A phase I study of an autologous GM-CSF-secreting breast cancer vaccine.
Authors: Anderson KS , Hodi FS , Sasada T , Canning C , Hassett M , Mayer E , Hannagan K , Wong J , Colson Y , Shoji B , Najita J , Sibani S , LaBaer J , Winer EP , Dranoff G
Published: December 2010

Abstract #4124

Background: Vaccination with tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) generates potent, specific, and long-lasting anti-tumor immunity in multiple tumor models. At DF/HCC, over 100 patients with melanoma, ovarian cancer, and lung cancer have been vaccinated. These studies have led to the identification of targets of immune-mediated tumor destruction. Here, we present analysis on the safety, feasibility, and biologic activity of an autologous GM-CSF-secreting breast cancer vaccine.  Methods:27 patients with metastatic breast cancer have undergone tumor procurement for vaccine from malignant pleural effusions (23), ascites (1), tumor nodules (2), lymph node (1), and 12 patients have received vaccine. Cells were transduced with a replication defective adenoviral vector encoding GM-CSF, irradiated, and GM-CSF secretion was measured by ELISA. Patients were required to have received at least one prior chemotherapy for metastatic disease and have an ECOG performance status 0-1. Vaccine was delivered s.c. and i.d. weekly for three weeks, then every other week. Immune monitoring included skin biopsies of vaccine sites, measurement of leukocyte populations, and proteomic-based assessment of antibody responses.  Results: Sufficient viable tumor cell yields for vaccination were obtained from all patients, with cellular yields ranging from 1.1-679 x 106 cells and viabilities ranging from 71-100%. Dose levels were based on cellular yield, ranging from 105 -107 cells/dose. The average yield of GM-CSF was 838 ng/106 cells/24 hrs (range: 24.4-5696), higher than the average yields for lung cancer and melanoma. Vaccinated patients were 34-69 years, and received 3-23 vaccines. 9 patients had progressive disease after 3-10 vaccines (1-4 months). One patient had stable disease after 23 vaccines (11 months), resumed vaccination at 16 months for progression and remains on study. One other patient remains on study, and one patient did not have measurable disease. Toxicities related to treatment include grade I/II local injection-site reactions, grade I/II inflammation at tumor sites as well as grade I/II fatigue, fever, nausea, and edema. Skin biopsies of vaccination sites revealed mild-moderate infiltration of lymphocytes, granulocytes, and macrophages.  Conclusion: Breast cancer cells can be harvested in sufficient number for autologous vaccine production from solid tumor as well as from malignant effusions. Autologous vaccination can induce coordinated immune responses with limited toxicity. The proteomic-based identification of antigen-specific immune responses following vaccination will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4124.
Hermodulins: bispecific ligand traps inhibit breast tumor growth and metastasis.
Authors: Turin L , Beryt M , Zhang J , Brdlik C , Jin P , Huang J , Bai X , Shepard H
Published: December 2010

Abstract #4127

Signalling by the human EGF (HER) receptor family can induce tumorigenicity and metastasis of cancer cells. Activation of these receptors has been associated with aggressive phenotypes and poor prognosis of breast cancer and other malignancies. Currently approved HER family targeted therapeutics are primarily directed against one member of the HER family.  We have engineered a family of bispecific (HER1:HER3) heterodimers comprised of a human IgG1-Fc fragment fused with modified extracellular domains of HER1 and HER3. These compounds, termed Hermodulins, act as “ligand traps” and inhibit ligand-stimulated activity of all members of the HER family. In this study we have shown that Hermodulins can inhibit in vitro growth and motility in breast cancer cell lines, act synergistically with other HER-directed tyrosine kinase inhibitors and monoclonal antibody therapeutics in tumor cell antiproliferation assays, and decrease the formation of osteolytic bone metastases in animal models.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4127.