bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Breast Cancer Risk Factors Do Not Improve Patient Acceptance of Chemoprevention.
Authors: Lo S. , Henry E. , Rychlik K. , Mumby P. , Bowling L. , Robinson P. , Albain K.
Published: December 2010

Background: Patients may be at increased risk of developing breast cancer due to hereditary or familial risk or a pathological diagnosis of breast atypia or lobular carcinoma in situ (LCIS). Although tamoxifen and raloxifene are effective and approved chemopreventive agents to reduce risk of developing breast cancer in high risk individuals, acceptance of chemoprevention as a risk reduction strategy is low. Our objective was to assess whether chemoprevention is more readily accepted by those at genetic or familial risk versus pathologic risk, and if the presence of multiple breast cancer risk factors improves chemoprevention acceptance.Methods: All patients seen at the Loyola University Cancer Risk Assessment and Prevention clinic completed information including demographics, health, family and social history. Patients with a family history of either a first or second degree family member with breast cancer (FH) were compared to those who presented due to atypia or LCIS on breast biopsy as well as those with an elevated Gail score. Acceptance of risk reducing strategies between these groups was compared.Results: The initial 115 patients presenting to the clinic were analyzed. Thirty-six (31%) women had FH only, 26 (23%) had a biopsy with atypia or LCIS only, 10 (9%) had an elevated Gail score, 17 (15%) had a biopsy indicating atypia or LCIS plus FH, and 26 (23%) had an elevated Gail plus FH. Seventy-three patients were candidates for chemoprevention; 16 (22%) accepted chemoprevention. Patients with a FH plus atypia/LCIS did not accept chemoprevention more than patients with FH alone (p=1.00). Patients with a FH plus atypia/LCIS did not accept chemoprevention more than than patients with atypia/LCIS alone (p=0.451). Pts with elevated Gail plus FH did not accept chemoprevention more than patients with elevated Gail alone (p=0.144). Four women in the FH group were known BRCA mutation carriers; all elected to proceed with risk reducing surgery, none accepted chemoprevention.Conclusions: Acceptance of chemoprevention is low in women at genetic or familial risk, those at risk due to atypia/LCIS, and those with an elevated Gail score. Having both familial and pathologic risk factors for breast cancer development did not increase acceptance of chemoprevention. Better understanding of women's comprehension of breast cancer risk, and barriers to patient acceptance of chemoprevention are needed.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1039.
Use of MMTV-Neu/P53 KO Transgenic Mice To Screen for Potential Chemopreventive Agents.
Authors: Grubbs C. , Juliana M. , Bode A. , Iwata K. , Ruppert M. , Lubet R.
Published: December 2010

The MMTV-Neu transgenic model of mammary cancer was developed almost 20 years ago in which the mice develop Neu over-expressing ER- mammary cancers. Since human ER- Neu over-expressing mammary cancers often also have mutations in P53, a heterozygous KO of P53 was incorporated into the model. We used this model to examine a wide variety of potential chemopreventive agents. The agents were administered to virgin female MMTV-Neu/P53 KO mice beginning when they were 60 days of age. Initiation of treatment with the agents was later than that typically employed by other investigators (e.g., 35 days of age). Mice were monitored until 360 days of age. In agreement with Brown and colleagues (e.g., Cancer Research 62, 6376-6380, 2002), it was found that both RXR agonists (Targretin, UAB-30) and EGFR 1 and/or 2 inhibitors (Tarceva, Lapatinib) were highly effective in preventing the development of these cancers. We also observed that a wide variety of agents were ineffective; including Atorvastatin, rosiglitazone (a PPAR gamma agonist), SAHA (an HDAC inhibitor), and a soy isoflavones mixture. In separate studies, mice bearing small palpable mammary tumors were treated for five days with these various agents, and examined for alterations in potential biomarkers; including proliferation. As previously shown by our lab in an ER+ rat model of mammary cancer, effective agents (e.g., Iressa and Targretin) strongly inhibited cancer cell proliferation, whereas ineffective agents failed to significantly inhibit proliferation. Thus, such a short-term assay might be employed to predict potential chemopreventive compounds. Short-term treatment with the EGFR inhibitors also decreased levels of expression of phosphorylated EGFR and downstream proteins; e.g., AKT/ERK. Thus, this model is useful in identifying agents that will prevent the development of human breast cancers that over-express Neu. This is important since Neu over-expressing ER- cancers have a relatively poor prognosis, and Neu over-expressing ER+ tumors are relatively unresponsive to standard hormonal therapies (e.g., tamoxifen and aromatase inhibitors). Supported by NCI contract HHSN261200433001C.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1042.
Surgical/Pathologic Breast Cancer Indicators: Adherence by the Florida Initiative for Quality Cancer Care (FIQCC) Consortium.
Authors: Laronga C. , Gray J. , Siegel E. , Ji-Hyun L. , Fulp W. , Jacobsen P.
Published: December 2010

Background: The FIQCC is comprised of 11 practice sites across the state that participate in a comprehensive review of quality of care specific to cancer patients across many disease sites. Quality indicators were scripted based on the accepted QOPI, NCCN, ACOS, and site-specific PI panel consensus indicators for breast cancer patients. An evaluation was done to assess adherence to performance indicators among the sites.Methods: Comprehensive chart reviews were conducted for all patients with breast cancer first seen in 2006 by a medical oncologist at one of the 11 FIQCC sites (3 academic/8 community). Quality measures included: 1) presence and completeness of the pathology report (tumor size, grade, specimen orientation, margins inked, margin status, receptor status); 2) documentation of surgery type (breast conserving vs. mastectomy); 3) documentation of sentinel lymph node biopsy (SLNB) and if SLNB positive for metastatic disease documentation of a complete axillary node dissection; 4) mammogram usage post surgery; and 5) referral to radiation. Statistical comparisons were performed using chi-square test.Results: Charts of 622 patients (99% female) with a median age of 60 years (range 22-95) were reviewed. With respect to pathologic reporting, there was strong compliance (>90%) for documentation of a pathology report, AJCC or TMN staging, tumor size and grade, status of margins, and receptor status. However, only 370 of 537 (69%) reports documented that the specimen was oriented and 474 of 537 (88%) stated the margins were inked. Breast conserving surgery was performed in 294 of 539 patients (55%). In clinical N0 patients, SLNB was performed in 447 of 543 (82%). Of the patients with a metastatic SLNB, 123 of 156 (79%) went on to have a complete axillary node dissection. Compliance was highly variable with obtaining a mammogram within 14 months of surgery (77%; range 26-98%). However, referral to radiation within 1 year was highly consistent (97%; range 80-100%). Significant variances across practice sites were noted for the reporting of margin orientation (p<0.001), inking of the margins (p<0.001), performance of SLNB (p<0.001), and obtaining a mammogram within 14 months of surgery (p<0.001).Discussion: The FIQCC allows for identification of the need for quality improvement in multiple aspects of breast cancer care. Findings based on 2006 cases identified a need for improvements in margin orientation and inking, use of SLNB and obtaining mammograms in follow-up after breast conserving surgery. These findings are now being used at the participating sites to guide quality improvement efforts.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1079.
Safety and Activity Report of a Randomized Phase II Trial of Preoperative Anthracycline-Based Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer: CHERLOB Trial.
Authors: Guarneri V. , Frassoldati A. , Bottini A. , Cagossi K. , Piacentini F. , Ravaioli A. , Cavanna L. , Amadori D. , Bisagni G. , Giardina G. , Conte P.
Published: December 2010

Introduction: We have designed a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or both trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage of pathological complete response (pCR) as defined as complete disappearance of invasive tumor in both breast and axillary nodes.Methods: chemotherapy (CT) consists of paclitaxel 80 mg/m2 weekly x 12 weeks followed by FE75C x 4 cycles administered every 3 weeks. Patients randomized to arm A receive CT plus weekly trastuzumab; in arm B patients receive CT plus lapatinib 1500 mg po daily; in arm C patients receive CT plus weekly trastuzumab and lapatinib 1000 mg po daily. Trastuzumab and lapatinib are administered throughout the entire CT plan. The study sample size has been calculated according to the two steps Simon's design. The overall planned accrual is 120 patients. Following the second safety report from the Independent Data Monitoring Committee on the first 30 evaluable patients, due to the occurrence of grade 3 diarrhea in 20% and in 41% of the patients randomized to arm B and C respectively, lapatinib doses have been reduced to 1250 mg in arm B and 750 mg in arm C.Results: 66 patients have been randomized: 20 in arm A, 20 in arm B, and 26 in arm C. Median age is 50 years (range 27-66). The overall non hematologic toxicity of grade (G) >1, as reported as maximum toxicity per patient, is as follows: diarrhea G2 29%, G3 22%; skin rash G2 29%, G3 7%; hepatobiliary events G2 10%, G3 5%, G4 3%.Left ventricular ejection fraction (LVEF) has been evaluated at baseline, after 12-13 weeks, and at the end of therapy. Mean LVEF% (range) was 62% (52%-77%), 61% (44%-78%) and 61% (53%-74%) respectively. No patient had symptomatic cardiac events. Forty-five patients underwent surgery, and are evaluable for response: 67% of the patients received breast conserving surgery. A pCR in breast and axillary nodes has been observed in 39% of the cases.Conclusions: The study accrual is ongoing. The safety of patients randomized following the amendment reducing lapatinib dosage will be presented at the Meeting. Supported by GlaxoSmithKline

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1093.
The Golgi Associated Calcium Pumps in Human Breast Cancer.
Authors: Grice D. , Faddy H. , Kenny P. , Monteith G. , Roberts-Thomson S.
Published: December 2010

The Golgi apparatus, located within the cell, is an intracellular calcium store. Golgi calcium is implicated in roles including post-translational modification, cell signalling and cellular proliferation. In breast cancer, there is evidence of aberrations in Golgi-dependent processes, some of which are linked to calcium regulated enzymes and Golgi structure. Previous studies show that Golgi-associated calcium pumps sequester calcium into the Golgi apparatus via an active transport mechanism requiring ATP. We investigated Golgi-associated calcium pumps in the context of breast cancer. Analysis of clinical breast sample and breast cancer cell line microarray databases indicates that different breast cancer subtypes may be characterized by alterations in Golgi calcium signalling. To explore this further, we assessed calcium transporter transcription in a bank of breast cancer-derived cell lines and non-malignant-derived breast cell lines using real time RT-PCR. The consequences of silencing Golgi calcium transporter expression were assessed using Dharmacon Smartpool On Target Plus siRNA. Inhibition (greater than 90%) was confirmed with real time RT-PCR 24, 72, 96 and 120 hours post transfection (P < 0.05). Effects of inhibition on calcium signalling, proliferation and induction and sensitization of breast cancer cells to endoplasmic reticulum stress via tunicamycin (0.1, 1, 10 µg/mL) was assessed. Endoplasmic reticulum stress was confirmed by measuring the induction of GRP94 mRNA expression. Effects on calcium signalling were characterized using a fluorescence imaging plate reader (FLIPR; Molecular DevicesTM) and a fluorescence calcium indicator. The nature of calcium responses to endoplasmic reticulum calcium mobilizing agents was assessed, agents included a sarcoplasmic-endoplasmic Ca2+-ATPase inhibitor, a purinergic agonist (ATP, 100 µM) and a protease activated receptor modulator. Collectively our results imply that some breast cancers are associated with a remodelling of Golgi calcium transport with functional consequences on calcium signalling in breast cancer cells. Modulators of Golgi calcium content in breast cancer may represent a novel therapeutic approach for some breast breast cancer subtypes.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1129.
An Investigation into a Panel of Isogenic Taxane Resistant Breast Cancer Cell Lines Using Transcriptomic and Genomic Methods.
Authors: Kenicer J. , Lambros M. , Sabine V. , Reis-Filho J. , Bartlett J.
Published: December 2010

Background: Taxanes are a powerful chemotherapeutics used to treat breast cancer. Taxane resistance has become increasingly more prevalent in the clinic; This problem is exacerbated by a lack of understanding of mechanisms underlying taxane resistance.Materials and Methods: 3 isogenic breast cancer cell-line panels: paclitaxel resistant (PACR) MDA-MB-231s/ZR75-1s and docetaxel resistant (DOCR) ZR75-1s were derived by culturing cells in incrementally escalating doses of taxanes over time. MDA-MB-231: native, 5nM, 25nM and 100nM PACR cells, ZR75-1: native, and 5nM, 25nM, and 50nM PACR and ZR75-1: native, and 5nM, 25nM and 50nM DOCR cells were analysed. RNA from native and PACR MDA-MB-231 cell lines was analysed on the Illumina® human ref.8V2 chip. Data were analysed using IlluminaGui. For aCGH, DNA was extracted from MDA-MB-231 PACR, ZR75-1 PACR and DOCR and respective parental lines, labelled and hybridised to a tiling path BAC microarray (resolution ∼50kb). Each cell-line was tested against reference samples of DNA from pooled female blood. Taxane resistant cells were tested against their parental cell line.Results: Illumina data demonstrated that resistance to increasing doses of paclitaxel is associated with sequential increases in mRNA dysregulation in MDA-MB-231 cells.A number of comparisons between the illumina data of native and the PACR cells were made using a p value of P≤0.001. The first comparison made using the illumina data, was between the 5nM PACR cells and the native cell lines: 25 significantly up or downregulated genes were identified. When the 25nM PACR cells were compared to the native cell lines, 225 genes were found to be significantly up or downregulated. Finally, when 100nM PACR cells were compared to native cells, 425 genes were found to be significantly up or downregulated. A group of genes identified that were common to multiple paclitaxel resistant groups included candidates such as YY1, AURKA and CCND2. aCGH has identified significant differences in patterns of copy number loss, gain and amplification in the taxane resistant cell lines, including chromosome loss of 6p and gain of 2p. Illumina and aCGH data were overlaid using specially designed algorithms.Discussion: Both aCGH and expression arrays highlight a progressive acquisition of molecular and transcriptomic alterations in isogenic breast cancer cell lines resistant to increasing doses of taxanes. Further mapping of transcriptomic and genomic profiles will enable identification of key molecular targets for restoration of taxane sensitivity. Genes upregulated in taxane resistant clones identified in the illumina experiment, in particular those whose upregulation is underpinned by DNA copy number gains in resistant cells, may represent genes which may be targeted with inhibitors to test potential candidates for reversing taxane resistance.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1134.
Frequency of PIK
3CA Mutations in Chinese HER2+ Metastatic Breast Cancer Patients and Association with Clinical Benefit to Lapatinib and Capecitabine Treatment.
Authors: Xu B. , Zefei J. , Chua D. , Shao Z. , Luo R. , Wang X. , Yuan P. , Newstat B. , Liu Y. , Gagnon R. , Chi H. , Martin A. , Stein S. , Wang L.
Published: December 2010

Background: Activating mutations in PIK3CA are frequent in breast cancer (Campbell et al. Cancer Res 2004;64:7678-7681). Previous analyses suggest that the presence of PIK3CA activating mutations were associated with poor clinical outcome (Li et al. Breast Can Res Treat 2006;96:91-95) and could confer resistance to treatment with trastuzumab (T) (Berns et al. Cancer Cell 2007;12:395-402). Lapatinib (L) is an oral tyrosine kinase inhibitor targeting EGFR and HER2 pathways. L plus capecitabine (C) has demonstrated efficacy in women with HER2+ metastatic breast cancer (MBC) previously treated with T (Geyer et al. N Engl J Med 2006;355(26):2733-2743). EGF109491 evaluated the efficacy of L+C in 52 Chinese HER2+ MBC patients. The clinical benefit rate (CBR) was 57.7% (PR 44% and SD 44%) and median progression free survival (PFS) was 6.3 months. The purpose of this analysis was to establish the frequency of PIK3CA mutations in this small cohort of Chinese patients and to determine if the presence of a PIK3CA mutation has any impact on clinical benefit to L+C.Methods: 38/52 patients provided tumor samples for biomarker analysis. Briefly, DNA was extracted from these tumor samples, amplified by PCR and sequenced by Pyrosequencing methods to identify the presence of frequent activating mutations in exons 9 and 20 in PIK3CA. Mutation status was tested for association with CBR and PFS using contingency table analysis and proportional hazards analysis respectively.Results:11/38 (29%) patients harbored a mutation in the PIK3CA gene, consistent with published frequencies. 9/11 mutations reside in the catalytic domain and 2/11 mutations reside in the accessory domain of the gene. There was no statistical association with CBR (p=0.639) or PFS (HR=1.01, p=0.989) in PIK3CA wildtype patients vs. PIK3CA mutant patients. PIK3CA wildtype n=27 (%)PIK3CA Mutation n=11 (%)CR0 (0)0 (0)PR12 (44%)4 (36%)SD13 (48%)5 (45%)PD1 (4%)1 (9%)Unknown1 (4%)1 (9%)HR1.01 (p=0.989) Conclusion: The frequency of PIK3CA mutations in this small cohort of Chinese HER2+ MBC patients is consistent with published frequencies. There was no statistically significant association between the presence of a PIK3CA mutation and clinical benefit to L+C in these patients. These results are in agreement with previous reports that mutations in PIK3CA do not seem to impact clinical outcome following L-containing treatment regimens.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1140.
The Isoform Selective Histone Deacetylase Inhibitor Entinostat Is Active in Primary Human Triple-Negative Breast Cancer Models.
Authors: Ordentlich P. , Hoffman J. , Doser T. , Tee L. , Huynh Y. , Mee S. , Mamuszka H. , Lee G.
Published: December 2010

Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an oral, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Previous studies have a) established the anti-proliferative activity of entinostat in the triple negative cell line model MDA-MB-231 b) shown that entinostat induces expression of ERα and c) that entinostat is synergistic with aromatase inhibitors to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to validate the activity of entinostat in highly predictive primary human tumor models of triple negative breast cancer.Methods: Two approaches have been taken. First, entinostat was tested in the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack ER, PR and HER2/neu expression by immunohistochemistry (IHC). Second, entinostat was tested at 5, 15, 30 mg/kg/d in two xenograft models using tissue derived directly from patient tumor resections. The breast cancer models MV4151 (from a postmenopausal patient with ductal invasive breast carcinoma) and MV4586 (from a premenopausal patient with relapsed invasive lobular breast carcinoma) were negative for ERa protein, however still positive for ERa mRNA. Both xenograft tumors did not express ERb. The tumor doubling times in nude mice were between 10 and 30 days. Both tumors are HER-2 negative (determined by IHC).Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 µM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested with IC50's ranging from 10nM to 270nM which are within the clinically achievable concentrations of entinostat. Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat inhibited (IC50 10-270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. < 50% growth inhibition at 2.45 µM). For the xenograft studies, at the time of writing, dose response data in the MV4151 model has demonstrated tumor growth inhibition by entinostat at the 15 and 30 mg/kg/d administered orally with no apparent weight loss. Ongoing experiments for which data will be presented include dose response in MV4586 as well as combinations with tamoxifen and fulvestrant in both xenograft models.Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors in human primary tumor models. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1146.
Computational Dissection of Tumor Expression Profiles.
Authors: Eklund A. , Juul N. , Li Q. , Richardson A. , Szallasi Z. , Szallasi Z.
Published: December 2010

Gene expression profiling has yielded important insights about tumor biology that may improve treatment decisions in patients. However, it is difficult to collect a specimen of pure tumor cells, and thus microarray measurements usually reflect the contribution of tumor cells as well as stromal and other normal cells. We applied unsupervised matrix factorization methods to gene expression data to derive several sets of co-expressed genes, or signatures, that together comprise a set of independent descriptors of breast tumors. Some of these signatures correspond to specific cell types (adipocytes, lymphocytes, fibroblasts), while others reflect well-known tumor-intrinsic expression programs (ER, ERBB2, proliferation). We confirmed the specificity of the signatures using expression data from purified normal cells and tumor cell lines, microdissected tumors, and bulk tumors with corresponding histological cellularity estimates. In several data sets, cell-type signatures were highly variable and anticorrelated with tumor-intrinsic signatures, confirming that variation in normal cell content is a potential source of measurement bias.Overall, these results provide an intuitive framework for the interpetation of tumor expression profiles and may lead to an improved understanding of the physiological mechanisms involved in tumor development.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1166.
Early Acquired Resistance to Endocrine Therapy: Extending the Neoadjuvant Model.
Authors: Anderson H. , Anderson H. , A'Hern R. , Salter J. , Hills M. , Detre S. , Larionov A. , Skene A. , Miller W. , Dixon J. , Smith I. , Dowsett M. , Dowsett M.
Published: December 2010

Background: Neoadjuvant endocrine therapy allows biological studies of de novo response and resistance but not of acquired resistance based on clinical endpoints as surgery is usually carried out after around 4 months. Response is associated with a significant fall in Ki67 (proliferation) after 2 weeks treatment. However, at 12/16 weeks, c.15% of tumours show recovery of Ki67. We hypothesized that this recovery reflected rapidly acquired treatment resistance and have assessed its clinical relevance and association with tumour biomarkers.Methods: Ki67, ER, PgR and HER-2 (with FISH for 2+ cases) IHC measurements taken at baseline, 2 weeks and 12/16 weeks during neoadjuvant aromatase inhibitor (AI) treatment were available from three previously reported clinical trials [1-3] for a total of 177 ER+ patients. To allow pooling of data, ER and PgR levels were expressed as Allred scores. Long-term clinical follow-up data were available for 142 patients who received endocrine therapy within the IMPACT trial. Categories of response/resistance based on Ki67 change were created and patients classified accordingly: de novo resistance (<50% decrease in Ki67 from baseline to 2 weeks), acquired resistance (>50% decrease in Ki67 from baseline to 2 weeks, but overall fall at 12/16 weeks <50%) and maintained response (>50% decrease in Ki67 from baseline to 2 weeks and overall fall >50%).Results: Patients defined as showing acquired resistance had significantly worse RFS than those defined as showing maintained response (HR: 3.73, 95%CI: 1.18-11.79, p=0.025) and very similar to those with de novo resistance (HR: 3.66, 95% CI: 1.41-9.50, p=0.008). More HER-2+ cases showed Ki67 recovery than would be expected by chance (acquired resistance: 5/19 HER-2+, maintained response: 5/100 HER-2+; p=0.02). There was a weak suggestion that pre-treatment ER level may be lower for patients showing Ki67 recovery than those with persistent response (p=0.11), but no evidence was seen for an effect of pre-treatment PgR level (p=0.52).Conclusions: Tumours that exhibit an early Ki67 fall followed by Ki67 recovery at 12/16 weeks are associated with poorer RFS than those showing maintained suppression of Ki67 suggesting that Ki67 may act as a valid intermediate marker of acquired resistance. HER-2 positivity is associated with development of early acquired Ki67-based resistance, but other mechanisms for early acquired resistance exist.Supported by The Mary-Jean Mitchell Green Foundation.[1] Dowsett M et al., J Clin Oncol 2005. 23(11): 2477-92[2] Smith IE et al., J Clin Oncol 2007. 25(25): 3816-22[3] Miller WR et al., J Clin Oncol 2009. 27(9): 1382-7

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2005.
Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer.
Authors: Bundred N. , Cramer A. , Morris J. , Landberg G. , Renshaw L. , Winter M. , Coleman R. , Grassby S. , Knox F. , Dixon M.
Published: December 2010

To determine whether the addition of Zoledronic Acid to endocrine therapy increases apoptosis or decreases proliferation in early invasive breast cancer, a placebo controlled randomised trial comparing 14 days treatment with Letrozole or Letrozole and Zoledronic Acid pre-operatively was performed.PatientsIn total 109 postmenopausal women with early invasive hormone receptor positive breast cancer were randomised (1:1:1) to either placebo, Letrozole 2.5mg/day or Letrozole with Zoledronic Acid 4mg single dose intravenously 2-4 days before definitive surgical excision. Epithelial proliferation and apoptosis were measured on paired baseline and surgical biopsy specimens (after 14 days of treatment) using Ki67 and Activated Caspase 3 immunohistochemistry. Alterations in angiogenic markers (VCAM/VEGF and CD31) were also studied. The primary endpoint was fall in Ki67 between diagnosis and surgical excision.ResultsOverall 109 women were enrolled but paired biopsies were only available for 101 patients. PlaceboLetrozoleLet + Zoln323435Absolute Ki67 change (median,range)-0.8 (-12,12)8.6 (-14,37)12.9 (-12,29)    Caspase 3 change (median,range)0.1 (-3.8, 9.3)0.4 (-2.7, -4.1)0.2 (-10.9, -14.4)    Absolute change (Cell turnover index)-0.3 (-142, -59)18.9 (-201, 192)17.7 (-14, 379) Statistically significant reductions in Ki67 and Cell Turnover Index were seen with Letrozole and Let & Zol (p ≤ 0.001) but there was no significant different between Letrozole and Letrozole plus Zoledronic Acid groups (p = 0.26). Apoptosis did not change between the three groups.ConclusionLetrozole reduces proliferation by 70% when used for 14 days prior to surgery. Zoledronic Acid administration prior to surgery is safe but when administered as a single dose at a median of 3 days before surgery did not significantly increase apoptosis or decrease proliferation compared to Letrozole alone.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2009.
Sunitinib (SU) in Combination with Trastuzumab (T) for the Treatment of Advanced Breast Cancer (ABC): Activity and Safety Results from a Phase II Study.
Authors: Blay J. , Lluch A. , Gutierrez M. , Martin M. , Kozloff M. , Prady C. , Huang X. , Verkh L. , Chen C. , Tassell V. , Kern K. , Verma S.
Published: December 2010

Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with single-agent activity in patients (pts) with heavily pretreated ABC (locally recurrent or metastatic breast cancer). T is approved for 2nd-line monotherapy and in combination with taxane-based therapies for 1st-line ABC. The combination of SU + T in HER2+ ABC pts was investigated.Materials and methods: Eligible pts with HER2+ ABC received a starting dose of oral SU 37.5 mg/d (continuous daily dosing [CDD]) and either T administered wkly (iv loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then q3w 6 mg/kg). Due to changing standard of care, the trial was amended to include pts having prior chemotherapy in the 1st-line setting. Previous treatment (tx) with T (± lapatinib) was permitted. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), pharmacokinetics (PK) and quality of life (QoL).Results: As of April 2009, 60 pts were enrolled (6 on the original protocol and 54 under the amendment). Of 54 pts enrolled post-amendment, 6 pts continue on study and 48 have discontinued, 12 due to AEs. Most (n=31; 57%) pts received SU + T as 1st-line tx and 11/31 pts were completely tx-naïve. Pts received a median of 5 cycles (range: 1–16) of SU and 4 cycles (range: 1–15) of T. SU was dose reduced from 37.5 mg/d to 25 mg/d in 39% of pts. All pts were evaluable for safety and 52 pts were evaluable for efficacy. ORR was 34.6% and clinical benefit rate was 48% (2 CR; 16 PR; 7 SD ≥24 wks). Of the 18 responders, 5 pts were completely tx-naïve and 9 pts were 1st-line. Median PFS was 25.3 wks (95% CI, 19.3, 29.1). Most AEs were G1/2. G3 non-hematologic AEs in ≥10% pts were asthenia (17%) and hypertension (11%) and 3 G4 events occurred (LVEF decline, pulmonary embolism, and pancreatitis). Hematologic AEs (G3/4 in ≥10% pts) were neutropenia (22%) and thrombocytopenia (17%). One G5 event (cardiogenic shock) was reported. LVEF decline/LV dysfunction occurred in 21 pts (6 pts had ≥G3 AEs); 18/21 pts (86%) had received prior anthracycline and 12 pts (57%) prior T. There was no significant on-tx change from baseline in the QoL domain. Mean (SD) steady state level for SU was 46.1 (25.9) ng/mL in agreement with prior observations.Conclusions: The combination of SU (37.5 mg/d; CDD schedule) + T (wkly or q3w) showed acceptable tolerability and antitumor activity in HER2+ ABC pts without adversely affecting overall QoL.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 201.
Gene Expression Profiling for Therapy Prediction in a Breast Cancer Neoadjuvant Therapy Study Applying Docetaxel/Epirubicin/Cyclophosphamide.
Authors: Kemming D. , Schlotter C. , Bosse U. , Vogt U. , Muhs H. , von der Assen A. , Brandt B.
Published: December 2010

Background: Gene expression profiling is a powerful tool to identify markers associated with clinical and therapy outcome of cancer patients. Prediction of the response to neoadjuvant regimens remains a persistent challenge. Aim of this ongoing study is the development of a gene set predicting the response of the tumor to a taxane- anthracycline based neoadjuvant chemotherapy.Material and Methods: Microarray expression profiling was performed on biopsy samples from patients before treatment using Human Genome Survey microarrays (HGSM). The protocol for a phase II study was elaborated for the treatment of breast cancer patients suffering from a primary tumor 1.5 cm or inflammatory breast cancer with Docetaxel/Epirubicin/Cyclophosphamide (TEC) prior to surgical treatment. The study was approved by the local ethical committee and all patients signed an informed consent.Results: Overall 80 patients have been enrolled in the presented study. High quality gene expression data were available from 58 patients. Of these patients 21 responded to the TEC regimen (pCR or MIB1 expressing cells in the residual tumor <= 5% and decrease of Mib1-expression >= 20%). Based on the gene-expression profile we were able to identify a preliminary gene set of 150 genes which allows us to separate responding tumors from the non responding ones based on their gene expression profile. A comparable separation of the groups could not achieved by established tumor markers, e.g. ER, PgR, HER2, uPA etc. which are measured simultaneously on the HGSM. Among the genes distinguishing the two groups several genes normally expressed in mononuclear blood cells were identified, pointing to the presence of tumor infiltrating leukocytes, predominantly in the tumors responding the TEC regimen. The presence of these cells has already been verified in a subset of the samples.Conclusion: We identified a gene set which allows to select patients who will benefit from neoadjuvant chemotherapy. Furthermore at least in the so far investigated samples tumor infiltrating leukocytes are significantly more often found in tumors which respond to a taxane- anthracycline based neoadjuvant chemotherapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2039.
Expression of Gene Trios as Predictive Markers of Response to Doxorubicin Based Primary Chemotherapy in Breast Cancer Patients.
Authors: de Camargo Barros Filho M. , Katayama M. , Brentani H. , Abreu A. , Oliveira C. , Góes J. , Barbosa E. , Brentani M. , Folgueira M.
Published: December 2010

Some studies have been carried out to identify a gene expression profile predictive of drug response in breast cancer patients and assessed the reproducibility of the model in an independent group of patients. In common, these studies have used the same technique already used to identify the panel of genes in a training set, to verify accuracy of the model in a validation set. We have previously identified through cDNA microarray technology gene trios whose expression was capable of predicting response to neoadjuvant chemotherapy based in doxorubicin and cyclophosphamide in breast cancer patients. We have now evaluated whether expression of these genes analyzed by real time RT-PCR, which represents a more accessible technique, would reproduce cDNA microarray results in separating responsive from non-responsive patients. Twenty eight samples, already studied by cDNA microarray, were analyzed as a technical validation group and subsequently, another 14 samples were evaluated, as a biological validation group. Expression of nine genes (defining five trio combinations, previously identified) was evaluated by RT-PCR in samples from the technical validation group, to define the separating plane, using linear discriminant analysis. Among the five trios, the best separation of tumors was conferred by RPL37A, XLHSRF-1 based trios (with NOTCH1 or NUP210, as third genes), which correctly classified 86% of samples from the technical validation group and 82% in a cross-validation analysis (leave-one-out). Next, samples from the biological validation group were spatially distributed using the pre-established features from these two trios, resulting in 71% correct classification. Additionally, other gene combinations were searched for a higher accuracy in discriminating response and expression of a new trio, RPL37A, SMYD2 and MTSS1, correctly classified 86% and 79% of samples from the technical validation (leave-one-out cross-validation) and the biological validation groups, respectively. Expression values evaluated by cDNA microarray and RT-PCR are reproducible, however they are not exactly the same as these methods are based on different technical principles and normalization approaches. Our data indicate that care should be taken when substituting techniques in an attempt to reproduce a model. In conclusion, expression of the gene trio RPL37A, SMYD2, MTSS1, as evaluated by RT-PCR, is a potential candidate as predictive marker of response to neoadjuvant chemotherapy in breast cancer patients.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2040.
Outcome of Invasive Lobular Carcinoma Compared to Infiltrating Ductal Carcinoma: A Population Based Study from British Columbia.
Authors: Al-Foheidi M. , Speers C. , Woods R. , Kennecke H. , Kennecke H. , Chia S. , Chia S.
Published: December 2010

Background: Lobular carcinoma is the 2nd most common invasive breast cancer histology after ductal carcinoma. Though phenotypically they are different, the two histologies are often treated the same with presumed similar outcomes. We sought to compare the baseline demographics, standard pathologic factors and long term clinical outcomes between lobular and ductal carcinoma from a large population based breast cancer registry.Methods: A retrospective cohort of referred patients to the BCCA with a diagnosis of stage I-III pure lobular or pure invasive ductal carcinoma from 1989-2000 was identified. Prior or synchronous breast cancers and cases with unknown grade were excluded. Standard demographic and pathologic factors was abstracted from the BCCA Breast Cancer Outcomes Unit database and compared between the two histologies. 10 year outcomes were calculated by Kaplan Meier method, with differences compared by log rank test. Median follow up for the entire cohort was 9.3 years.Results: A total of 13,203 individual patients meeting identified inclusion criteria were identified: 11,911 invasive ductal and 1,292 invasive lobular cancers. Lobular carcinomas generally had a higher frequency of poor prognostic factors: older age (≥ 70 years old), larger tumour size, and greater frequency of N2 nodal involvement (all p<0.001). However lobular carcinomas also had a higher frequency of better predictive factors: ER+ status and low grade tumours (both p<0.001). There were differences in locoregional treatments and systemic therapies between the groups. No differences were seen at 10 year estimated relapse free survival (76% vs 74%), distant RFS (78% vs 77%), breast cancer specific survival (81% vs 81%) and overall survival (69% vs 70%) between lobular and ductal cancers respectively. Only 10 year locoregional RFS significantly favored lobular cancers (93% vs 89%; p<0.001), though there was also a higher mastectomy rate (55% vs 39%) in this cohort.Conclusion: Though invasive lobular carcinomas are epidemiologically and phenotypically different from ductal carcinomas, clinical outcomes are comparable between these two common histologies.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2046.
Characteristics of Overall and Cause-Specific Survival Rates in Breast Cancer Patients under the Age of 40: A Population Based Study of 481,294 Cases in SEER Registry.
Authors: Kim E. , Thomas, Jr C. , Hoffelt C.
Published: December 2010

Background: Age at diagnosis has been shown to be an important prognostic factor of outcome for breast cancer (BCA). The specific aim of this study was to determine the overall survival (OS) and cause-specific survival (CSS) in young patients (<40 years old) with BCA relative to older age groups.Methods & Materials: The population of this study comprised of the 481,294 cases of women with BCA extracted from the Surveillance, Epidemiology, and End Results (SEER) registry from 1973-2006, and restaged BCA cases according to AJCC 6th edition staging system. OS and CSS were determined by the Kaplan-Meier method using R. Statistical significance was tested using the log rank or Mantel-Haenszel test in R.Results: The total 481,294 cases were categorized into the following stage groups: Stage 0 (36,692, 7.6%), I (243,460, 50.6%), II (135,013, 28.1%), III (50,233, 10.4%), and IV (15,896, 3.3%). The range of ages was from 11 to 106 (mean 60.5). Ages were divided into 5 groups: <40 (25,918, 5.4%), 40-49 (89,712, 18.6%), 50-59 (116,548, 24.2%), 60-69 (110,536, 23.0%), and >69 (138,580, 28.8%) years old. A graph of OS and tables for OS and CSS from Kaplan-Meier analysis of the entire cohort (all stages) is shown below:OS (all stages) by Age GroupAges \ OS5-year10-year15-year<40.849.764.71440-49.899.830.77550-59.890.810.72560-69.863.728.576≥70.731.479.253 CSS (all stages) by Age GroupAges \ CSS5-year10-year15-year<40.680.785.74240-49.913.859.82550-59.914.864.82560-69.916.860.814≥70.887.820.762 Both OS and CSS of each stage group shared the same trends as in the analysis of the entire cohort.Conclusion: The OS of the <40 year age group was statistically significantly better than the 60's and >69 year age groups, but worse than the 40's and 50's age groups. The CSS of the youngest age group was significantly worse than all age groups except the >69 age group. Further studies to determine contributing variables for these observatios is warranted.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2048.
Breast Cancer Survival of Elderly Women in the Netherlands (1994-2005).
Authors: Bastiaannet E. , de Craen A. , Liefers G. , van der Geest L. , Westendorp R. , van de Velde C.
Published: December 2010

Purpose of the study: Breast cancer is the most commonly diagnosed malignancy in elderly women. With an increasing life expectancy of Western populations and increasing incidence of breast cancer, it is one of the major health concerns in the geriatric population. Aim of this study was to assess time trends in relative survival of elderly breast cancer patients in the Netherlands as compared to the younger patients and compare expected and observed mortality in the Dutch population.Methods: Female breast cancer patients 15 years and older, diagnosed with their first primary breast cancer from 1994-2005, were selected from the Netherlands Cancer Registry (NCR). Relative survival was calculated by the Hakulinen method as the ratio of the survival observed among the cancer patients and the survival that would have been expected based on the corresponding (age and year) general population. National life tables were used to estimate expected survival. Relative Excess Risks of death (RER) over time according to age were estimated using a multivariate generalized linear model with a Poisson distribution, based on collapsed relative survival data, using exact survival times.Results: Overall, 127 805 patients were included. Relative survival (5-years) declined from 87.1% for 15-65 years old to 86.1% (65-74), 74.7% (75-84) and 68.4% for 85 years and older. From 1995-2005 relative survival did increase for the young patients (RER corrected for stage, histology, treatment and grade 0.93; p<0.001) and for 65-69 (RER 0.93; p<0.001), 70-74 (RER 0.97; p=0.005) and 75-79 (0.98; p=0.03) years old. However, relative survival did not increase significantly for elderly patients of 80 years and older. Relative survival was higher for patients younger than 70 years and the difference in (corrected) RER for elderly versus young patients did increase over the years from 1.22 to 1.69 (p<0.001). Stratified for stage the differences were most striking in the higher stages. Differences between observed and expected mortality decreased with increasing age.Conclusion(s): The gap in breast cancer survival between young and elderly (>70) patients has increased in the Netherlands and survival for patients of 80 years and older has not improved. Despite growing degree of interest, internationally agreed evidence-based guidelines for the elderly with breast cancer do not exist. The aim of the FOCUS study that recently started in the Netherlands is to develop clinical guidelines for the elderly females with breast cancer using population-based, clinical trial and molecular data.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2052.
Physical Activity Levels of Women Attending Glasgow Breast Clinics.
Authors: Tan A. , Pavlidou E. , Ogston K. , Doughty J. , Wilson C. , Campbell A. , Tovey S.
Published: December 2010

IntroductionEpidemiological studies suggest that moderate intensity recreational physical activity (PA) improves breast cancer survival. We aimed to assess the current levels of PA in breast cancer survivors and a cohort of women with benign disease attending clinics in Glasgow.Materials and MethodsPatients at breast clinics at the GRI and WIG were recruited over a 5 week period. Data on physical activity levels (occupational, household, recreational) over the 7 days were recorded using the International Physical Activity Questionaire (IPAQ).ResultsA total of 352 patients were recruited with 141 (40.1%) of the patients completing the questionnaire successfully (table 1).Table 1  Women attending symptomatic clinicBreast cancer survivorsNo. patients 9742Median Age 4263Average physical activity levels (MET-Hr / Week)Total11493.4 Physical19.619.7 Household35.740.0 Occupational40.523.9 Recreational PA appears to be the major influence on breast cancer survival (1) and the reported MET-hr/week for each cohort are shown in table 2.Table 2Recreational Physical activity levels (MET-Hr / Week)Women attending symptomatic clinicBreast cancer survivors<533 (34%)21 (50%)5 - 1014 (14%)5 (12%)10 - 1918 (19%)8 (19%)>1932 (33%)8 (19%) DiscussionScottish guidelines (2) suggest 30min of moderate exercise most days a week is beneficial (>10MET-hr/week) but over 60% of our patients were not achieving this. A recreational PA level of >5MET/hr/week has been demonstrated to confer a benefit on breast survival (1). However 50% of our breast cancer survivors are not meeting this relatively modest target (equivalent to 1hr15min moderate activity/week). With the planned implementation of an exercise programme for all newly diagnosed breast cancer patients in Glasgow, we hope to improve levels of recreational physical activity and will re-audit following its introduction.References1. Friedenreich CM, Gregory J, Prospective cohort study of lifetime physical activity and breast cancer survival. Int J Cancer. 2009 Apr 15;124(8):1954-622. Let's Make Scotland more active: A strategy for physical activity. Physical activity task force http://www.scotland.gov.uk/Publications/2003/02/16324/17895 [Online March 2009]

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2066.