bluuebunny/crossref_metadata_2025 huggingface dataset:
P5-05-06: Dysregulation in the Transport of Iron and Haem Is Implicated in the Aetiopathogenesis of Breast Cancer.
Authors: Roe T , Hoar F , Tselepis C
Published: June 2012

Backround: Mounting evidence implicates iron in the development of a number of cancers, including breast. The responsible mechanism is poorly understood in breast cancer, although recent work has demonstrated irregular expression of various molecular iron transporters.

Materials and Methods: Immunohistochemistry on archived material was used to evaluate differences in expression of iron and haem exporters, importers and storage proteins between breast cancer, DCIS and normal breast tissue. The results were corroborated by Western blotting and RT-qPCR on protein and RNA samples generated from matched normal and cancer specimens collected at mastectomy. The ability of benign and malignant breast cells in vitro to accumulate excess iron in the presence of exogenous iron/haem was evaluated with a ferrozine assay. In addition the effect of exogenous iron and haem on cell phenotype in vitro was assessed in benign and malignant cell lines. Assays utilised included viability (MTT), proliferation (BrdU), migration, anchorage-independent growth (colony formation) and invasive capacity. These assays were then repeated in the presence of iron chelators to investigate their potential utility as a therapeutic modality.

Results: Statistically significant increases (p<0.05) were observed in expression of the iron importers DCytB, DMT1 and TfR in breast cancer relative to normal tissue. Levels of the storage protein ferritin were also significantly raised. The iron exporters ferroportin and hephaestin were significantly under-expressed in breast cancer, while hepcidin (which induces exporter degradation) was over-expressed. Levels of the haem importer HCP1 and the exporters BCRP and FLVCR were all significantly down-regulated in cancer relative to normal.

Both benign and malignant breast cells were capable of importing excess iron, although only malignant cells could import excess haem. Iron induced increased viability and proliferation in benign cells but had no effect on their migratory or invasive capability, or their ability to form colonies. Haem had no effect on benign cell phenotype. Iron and haem both had significantly positive effects on all these aspects of cell phenotype when introduced to malignant breast cells in vitro. Iron chelators were capable of abrogating these positive effects.

Discussion: Archived material and prospectively collected matched tissue pairs demonstrate that breast cancers exhibit altered expression of the proteins involved in transporting iron and haem through the cell. In vitro experiments reveal malignant cells to be capable of taking up both substances, which both appear to drive a more malignant phenotype. These in vitro changes can be reversed through the introduction of iron chelators, implying possible efficacy as a novel therapy in breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-06.
P5-06-01: Gene Expression Analysis of Resistance to Bevacizumab in a VEGF-Reinforced Xenograft Model of ER-Positive Breast Cancer.
Authors: Gökmen-Polar Y , Toroni RA , Goswami C , Sanders KL , Mehta R , Sirimalle U , Tanasa B , Shen C , Li L , Ivan M , Badve S , Sledge GW
Published: June 2012

Background: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), had promising therapeutic efficacy in breast cancer. However, intrinsic or acquired resistance is common in the clinic. To improve our understanding of the underlying mechanisms of resistance to bevacizumab (BEV), we report the gene expression analysis of resistance to bevacizumab in a VEGF-overexpressing xenograft model of ER-positive breast cancer.

Methods: We developed a nude mouse xenograft model of resistance to anti-VEGF therapy with BEV in which MCF-7 control (ML20) or MCF-7 VEGF (MV165) transfectants were implanted in mammary fat pads, allowed to grow, then treated with BEV, with collection of tumor at early or late time points (while responding (R) to or progressing (NR) on anti-VEGF therapy). To elucidate differentially expressed gene profiling associated with tumor resistance to BEV, we performed whole-genome gene expression analysis (Human WG-6v2 Expression Beadchips, Illumina) and miRNA profiling (TaqMan ***ArrayHuman MicroRNAA+B Cards Set v3.0, Applied Biosystems). Validation of the chosen genes was performed using quantitative real-time RT-PCR (qRT-PCR).

Results: Gene expression analysis revealed differentially regulated genes in the MV165-NR group compared with the MV165-R group. Among the significant genes, Follistatin (FST) and HEY2 were the top genes upregulated in NR compared to R by ANOVA. Expression of HEY2 is induced by the Notch signaling pathway. Using qRT-PCR, we validated the expression of FST and Notch in our system. FST was significantly decreased (Fold change= −3.2; P=0.03) in the R group compared with vehicle in MV165 xenografts. In contrast to R group, FST was upregulated significantly (Fold change= 9.3; P=0.05) in the NR group. Notch4 displayed increased levels of expression in NR group, but it did not reach significance (P=0.23). In addition, correlation of mRNA and miRNA profiles showed that miRNAs targeting FST and Notch4 were differentially regulated in NR group compared to R group in MV165 xenograft tumors. Among the miRNAs, TGF-β-induced oncomiR miR-181a is up-regulated in NR and targets both FST and Notch4. Other miRNAs that target both Notch4 and FST include miR-1, miR-133a, miR-133b, and mir-449b. Conclusion: Our data serve as a potential mechanistic explanation for acquired resistance to bevacizumab. These data may shed light on the transitory effect of BEV observed in the E2100 firstline metastatic breast cancer trial, where VEGF-targeted therapy prolongs progression-free survival in metastatic breast cancer without improving overall survival.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-01.
P5-08-01: Quantitative Analysis of Strain Ratio of Microcalcification Lesions with Surgical Specimen Mammography.
Authors: Hung S-H , Chen R-C , Wu Y-T , Chen T , Lin C-H
Published: June 2012

Measurement of the strain induced by compression can be useful in the diagnosis of breast tumors. Microcalcification (MC) detected by mammography could be the only symptom of early breast cancers. The purpose of this study was to develop a quantitative method for a differential diagnosis of MC lesions based on the strain ratio (SR) obtained by applying different breast compression pressure during mammography.

Methods: This prospective study was conducted with institutional review board approval and the written informed consent was obtained. Twenty-five mastectomy specimens (24 for treatment of breast cancer and 1 from contralateral prophylactic mastectomy) with MCs were examined by digital mammography. There were 24 malignant MCs (mean size of 18.8 mm) detected in the 24 separate specimens, including 14 lesions of invasive carcinoma and 10 lesions of carcinoma in situ. Five benign MCs (mean size of 21.6 mm) were detected, including four lesions which coexisted with malignant MCs in the four separate specimens, and one was discovered in the prophylactic mastectomy specimen. Each specimen experienced four different magnitudes of compression force and the corresponding images were acquired for further analysis. Images in Digital Imaging and Communications in Medicine format (DICOM) were exported into custom software, written in Matlab, to contour the region of interest. Stress was defined as the force divided by the whole specimen area, and the square root of MC area was calculated to represent strain deformation. The SR was the slope of the best-fit line through the four points of each lesion. Histology of the MC was correlated with SR. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of SR for discrimination between benign and malignant MC.

Results: The SRs were higher in the malignant MC group (139.10 a.u.) than in the benign MC group (34.09 a.u.; p = 0.024). The SR between invasive carcinoma and carcinoma in situ showed no statistic significance (127.03 a.u. vs. 156.00 a.u.; p = 0.642). The area under the ROC curve for the diagnosis of benign and malignant MC was 0.825 (95% CI, 0.667 to 0.982).

Conclusion: This study demonstrated that the SR detected by mammography showed potential for distinguishing benign from malignant MCs. Further in vivo investigations of larger cohorts are necessary to validate these results.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-01.
P5-09-05: Non-Palpable Lesions Findings in a Breast Cancer Opportunistic Screening in South Brazil.
Authors: Rockenbach R , Rombaldi RL , Caleffi M
Published: June 2012

Introduction: Today breast cancer is a major public health challenge in developing countries with increasing mortality rates due to the lack of early detection programs and access to care. Mammography has been considered the most sensitive test for breast non-palpable lesions. The Brazilian National policy recommends mammography from age 50 and every two years. This study investigates only radiological findings in a set of women seeking for long term breast care surveillance.

Objectives: To evaluate patients characteristics of cases with non-palpable breast lesions.

Material and method: A prospective and transversal study was undertaken between March,2009 and April,2010 on 110 women with non-palpable breast lesions, diagnosed by mammography or ultrasound. Histo-pathological evaluation was performed in core biopsy specimen. The following variables were studied: pregnancy, parity, menarche, menopause, hormone replacement therapy, breast lesion location, tumor size, histopathology findings, mammographic and ultrasound classification — BI-Rads.

Results: 23,7% (n=26/110) out of 110 women were diagnosed with breast cancer and 76,3% (n=84/110) were diagnosed with benign mammary pathology. Mammography, according BIRads classification, strongly suggested (p<0,000) the presence of benign and malign pathologies. In the breast cancer group, 14 were diagnosed with stage 1 (TNM), compared to the official data from INCA where stage I is 10% of the cases.

Conclusion: Mammographic screening reduces mortality by 30% after 50 years of age and also provides important benefit (20%) in younger women (40-49). Our study showed a cancer detection rate of 25,7% and 34,6%, respectively, demonstrating the importance of screening also in younger ages. Overall, the rate of biopsy positive was very satisfactory (1 out of 4 cases). Among the studied non-palpable breast lesions, our findings resulted in 53.8% stage I breast cancers (TNM) which reinforces the urgent need of a structured screening program in Brazil to save more lives.

Financial support: Avon Institute.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-09-05.
P5-13-01: Survival Outcome with Bevacizumab: Activation of the Phosphatidylinositol-3 Kinase (PI3K) Pathway Due to PIK3CA Mutations or PTEN Loss Makes a Difference.
Authors: Vidal M , Di Cosimo S , Torrejon D , Saura C , Gómez-Pardo P , Pérez-Garcia J , Muñoz-Couselo E , Bellet M , Sanchez-Olle G , De Mattos-Arruda L , Oliveira M , Tabernero J , Baselga J , Cortes J
Published: June 2012

Background

The PI3K pathway is known to regulate the transcription of Vascular Endothelial Growth Factor (VEGF) in endothelial and cancer cells. The inhibition of VEGF is the rationale behind the development therapy with anti-angiogenics. We investigated the activation of PI3K pathway, defined as PTEN loss and/or PIK3CA mutations, and the relationship with survival in metastatic breast cancer patients treated with the anti-VEGF monoclonal antibody bevacizumab.

Patients and methods: Records for patients with HER2 negative metastatic breast cancer (MBC), treated with bevacizumab from July 2005 to June 2010, and with known PI3K status were reviewed. Univariate and multivariate analysis were performed using SPSS 15.0.

Results: A total of 40 patients — 26 with and 14 without PI3K activation — were identified. Median age was 47 years (range 27–79). Median overall survival (OS) was 41.23 months (CI 95%: 27.29 — 55.18) and 66.23 months (CI 95%: 61.04 — 71.42) in patients with and without PI3K activation, respectively (p=0.04). Among patients with PI3K activation, OS was 34.13 months (CI 95%: 22.40 — 45.86) and 43.43 months (CI 95%: 26.9 — 59.97) in cases with PIK3CA mutations and PTEN loss, respectively. As compared to patients without PI3K activation, patients with PI3KCA mutations but not patients with PTEN loss showed a significant worse outcome (p=0.006 and p=0.3, respectively). In the multivariate analysis including grade, hormone receptor and Ki67 status, and total lines of treatment, the activation of PI3K activation proved to be an independent prognostic factor (p=0.03).

Conclusions: The activation of the PI3K pathway is significantly associated with decreased OS of MBC patients treated with bevacizumab. Prospective evaluation of PI3K activation on VEGF signaling with differential implication of PI3KCA and PTEN loss is warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-01.
P5-13-03: Correlation of Clinical and Molecular Findings with Pathologic Response to Preoperative Lapatinib and Trastuzumab, Separately or in Combination, Prior to Neoadjuvant Chemotherapy for HER2 Positive Breast Cancer.
Authors: Holmes FA , Espina V , Liotta LA , Chang JC , Nagarwala YX , Danso M , McIntyre K , Osborne CR , Krekow LK , Gagnon RC , Mahoney JM , O'Shaughnessy JA
Published: June 2012

Background

15% of curative HER2−positive patients (pts) treated with standard trastuzumab (T)-based chemotherapy regimens recur. Our prior report (ASCO 2011 #506 using only data from paired samples N=49) identified major pathways of resistance: autophagy, stem cell, extracellular matrix, and phospho epitopes on FOXO, STAT5, EGFR.

Aim: To collect proteomic and microarray data from baseline biopsies and identify molecular correlates of pathologic complete response (pCR).

Methods: Randomized, open label, phase II. Eligibility: biopsy-proven HER2 positive stage II, III invasive breast cancer, healthy. After informed consent, pt randomized to T or Lapatinib (L) or both (T+L) for 2 weeks (wk) then continue same anti-HER2 agent with standard chemotherapy (FEC75 IV every 3 wk then Paclitaxel 80 mg/m2 wk x 12) then surgery. Research biopsy before and 2 wks after anti-HER2 agent analyzed by reverse phase protein microarray (RPMA) from laser capture microdissected cells, RNA expression microarray, and in-vitro stem cell studies. PCR in breast is no invasive tumor. ITT is Intent to Treat (all treated pts). Pathways identified by analytes (n=42): autophagy (Beclin 1, LC3B, ATG5), stem cell (CD44, Mushashi, E-Cadherin, Beta Catenin), extracellular matrix (Integrin, MMP). Additional informative analytes: phosphorylated HER3, IGFR1.

Results: 100 pts treated: T=33, L=34, T+L=33. % pCR- ITT: ER pos/ER neg by arm: T = 40%/67%; L = 21%/50%; T+L = 58%/50%. Baseline RPMA samples N= 65 (T = 22; L= 25; T+L = 18). A) Specific analytes contributory to outcome by arm by Random Forest analysis: T: Beta Catenin Ser 33/37/Thr 41, EGFR Tyr1045. L: MMP14, E-Cadherin, LC3B, Integrin alpha5 B1, Stat 5 Tyr 694, IGFR Tyr 1131/1146, Erk Thr 202/Tyr204, NFKB Ser536, FOXO Thr24, HER3 Tyr1289. T+L: cerb2, EGFR, Met Tyr1235, CD44, E-Cadherin. B) Statistically significant endpoint ratios from network analysis that strongly correlate with pCR: T: HER3 Tyr1289/Beclin 1; PTENser380/ERK Thr202/Tyr204; GSK3B Ser21-9/Stat5 Tyr694; p70S6 Thr389/LC3B; p7026 Thr389/MMP9; FOXO Thr24-32/NFKB Ser536; Beta Catenin Ser 33–37 Thr41/LC3B. L: EGFR Tyr1045Beclin1; cerb2/Beclin1; HER3 Tyr1289/Beclin1; PI3K/FOXO Thr24,32; IRS1 Ser612/Beclin1; Mushashi/IRS1 Ser612. T+L: only 4 pts no pCR. C) Microarray analysis confirms the critical role of extracellular matrix and autophagy.

Discussion: These findings support the concept that NO-pCR tumors can engage a diverse set of strategies to achieve cell survival in the face of therapy. The molecular correlates of response found in this small, underpowered study provide candidates for future patient stratification studies and generate insights for combination therapy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-03.
P5-13-11: PTEN and Tau-Protein Expression: Predictive Value of Poor Response to Trastuzumab Plus Paclitaxel in Patients with HER2−Positive Breast Cancer.
Authors: Koo DH , Ahn J-H , Yoon DH , Kim S-B , Lee HJ , Kong KY , Son BH , Ahn SH , Jung KH
Published: June 2012

Backgrounds: Trastuzumab-based chemotherapy has been an active treatment in patients (pts) with HER2−positive breast cancer; however, primary and secondary resistance has occurred in pts treated with trastuzumab (H) alone or in combination with chemotherapy. Material and Methods: Biomarkers were searched using tissue microarrays (TMA) in the HER2−positive breast cancer pts treated with H and paclitaxel (P) combination chemotherapy between October 2004 and August 2010. Tumor blocks of 101 pts were analyzed for VEGF, IGF-1R, p-Akt, beta-III tubulin, CD44, Tau-protein, p27 and PTEN by immunohistochemical (IHC) analysis. Eight biomarkers were assessed to investigate the correlation with the clinical outcomes, including response rate (RR), progression free survival (PFS), and overall survival (OS).

Results: With a median follow-up duration of 21.7 months (range, 9.1−55.2 months), 101 pts received H+P chemotherapy in neoadjuvant setting (n=36, 35.6%) and recurrent or metastatic setting (n=65, 64.4%). Median age was 48 (range, 19–83 years), and the majority of pts (n=95, 94.1%) had good performance status. Premenopausal pts and hormone receptor-negative pts were 48 (47.5%) and 52 (51.5%), respectively. The median cycle of H+P chemotherapy was six (range, H 1–43; P 1–21). Overall RR was 68.3% (n=69) including complete response with 7 pts, and PFS and OS were significantly longer in pts responsive to H+P chemotherapy compared with non-responsive patients (PFS, p=0.001; OS, p=0.015). Although VEGF, IGF-1R, p-Akt, beta-III tubulin, CD44, p27 and PTEN status by IHC were not significantly associated with response to H+P chemotherapy, Tau-protein showed a trend of association without statistical significance (RR, 46.2% vs. 71.6%, p=0.066). Among 13 pts with high Tau protein expression, 9 pts with both high Tau-protein and low PTEN level showed statistically significant lower RR compared with other 92 pts (22.2% vs. 72.8%; p=0.002). None of the biomarkers was related to PFS and OS in pts with recurrent or metastatic disease, and to pathologic complete response in pts after H+P chemotherapy as neoadjuvant therapy.

Conclusion: Our data showed that both low PTEN level and high Tauprotein expression were significantly associated with poor response to H+P chemotherapy in patients with HER2−positive breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-11.
P5-14-08: Impact of Progesterone Receptor Semiquantitative Immunohistochemical Result on Oncotype DX® Recurrence Score: A Quality Assurance Study of 1078 Cases.
Authors: Bhargava R , Dabbs DJ
Published: June 2012

Background: The oncotype DX® recurrence score (RS) is predominantly dependent on estrogen and progesterone receptor content of the tumor, proliferation and HER2 status. We have previously shown (Mod Pathol. 2008;21:1255–1261) that using a regression equation that incorporates the above along with tumor grade components is capable of estimating the RS [RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) −0.045 (ER immunohistochemical score) −0.030 (PR immunohistochemical score) +9.486 (HER-2/neu)]. Subsequent studies have also shown similar findings including a few that suggests an even more important role for progesterone receptor. In order to identify the role of semiquantitative progesterone receptor immunohistochemical (IHC) result in a simplistic manner, we evaluated the PR IHC score (H-score) for different categories of RS (low, intermediate, and high) within each tumor grade (I, II, III).

Design: As a continuing quality assurance program at our institution, all cases sent for oncotype DX® testing that have available tumor grade, and RS were included in this study. Hormone receptor results at our institution are reported using an H-score like method which details the percentage of positive cells showing none, weak, moderate, or strong staining. The score is given as the sum of the percent staining multiplied by an ordinal value corresponding to the intensity level (0=none, 1=weak, 2=moderate, 3=strong). With four intensity levels, the resulting score ranges from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).

Results: A total of 1078 cases were analyzed (see table below).

Conclusions: Within each grade, PR IHC score is inversely related to the RS. The dramatic impact of PR IHC score on RS is noteworthy. If PR IHC score is combined with traditional histopathologic features (nuclear grade, mitotic activity score), and other IHC variables (ER IHC score, HER2 status, Ki-67 labeling index), then a tumor's risk of recurrence and need for chemotherapy can be reasonably estimated. Oncotype DX® test may not be necessary in more than half of cases that are currently sent for testing.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-08.
P5-14-24: The Long Term Prognostic Impact of Real-Time Quantitative RT-PCR Detection of Cytokeratin 19 mRNA in Preoperative Bone Marrow Aspirates of Early Breast Cancer Patients.
Authors: Punie K , Wynendaele W , Clement P , Paridaens R , Christiaens M-R , Jacobs B , Wildiers H
Published: June 2012

Purpose: Several studies have evaluated the prognostic effect of bone marrow micrometastases at the time of surgery in early breast cancer, but few studies have long term outcome data. We report here a cohort with more than ten years follow-up.

Materials and methods: 131 patients with primary operable invasive breast cancer were enrolled in the protocol from February 1998 to September 1999. Bone marrow aspirates, obtained from the iliac crest or the sternum, were analyzed with real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) for the presence of cytokeratin 19 (CK19) mRNA. All patients received standard therapy and follow-up. After a median follow-up of 133 months, data about disease recurrence (invasive disease free survival, IDFS) and survival (breast cancer specific survival (BCSS) and overall survival (OS)) were collected. A control group consisted of archived cDNA samples from 38 patients with hematological malignant antecedents in complete remission and without known gene arrangements. The upper limit of the 95% confidence interval of the level of CK19 positive cells is this group was used as cut-off (260 cytokeratin 19+ cells / 5 × 106 leucocytes) to determine bone marrow status in breast cancer patients.

Results: 69 bone marrow samples from breast cancer patients (52,7 %) were considered CK19 positive. IDFS was 60.9 % and 79 % for CK19+ and CK19- patients, respectively (log-rank p-value = 0,036). When CK19 was evaluated as a continuous variable, IDFS also correlated significantly with the level of CK19 mRNA in bone marrow aspirates (p-value = 0,019). Except for lymph node status (ANOVA linear regression p-value = 0.022), there was no significant correlation between the level of CK19+ cells in the bone marrow and classical prognostic factors (pathological tumor stage, tumor size, differentiation grade, hormonal receptor status).

In multivariate Cox-regression analysis correcting for tumor size, differentiation grade, lymph node status, hormone receptor status, tumor stage and treatment modalities (surgical procedure, chemotherapy, radiotherapy and antihormonal therapy), the CK19 bone marrow status still was a significant predictor of IDFS. (p-value = 0.042)

Differences in BCSS (78 % of CK19 + patients and 84 % of CK19 — patients) and OS (75 % in CK 19 + patients and 74 % in CK 19 — patients) were not statistically significant. (log rank p-values 0.087 and 0.883, respectively).

Conclusion: This study demonstrates the long term (>ten years) prognostic effect of CK19 mRNA detection with RT-PCR in the bone marrow of operable breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-24.
P5-15-03: Development of a Patient Decision Aid for Women 70 Years and Older with Stage I, Hormonally Sensitive, Breast Cancer Considering Adjuvant Treatment Post-Lumpectomy.
Authors: Szumacher E , Wong J , D'Alimonte L , Angus J , Paszat L , Metcalfe K , Whelan T , Llewellyn-Thomas H
Published: June 2012

Background: Decision Aids (DA) are developed with the intent to support people in making specific and deliberate choices by improving information transfer about different outcomes. Previous research has shown that DAs can increase patient knowledge regarding treatment options, reduce decisional conflict, and increase patient satisfaction with the decision-making process. However, no DAs have been developed to help older breast cancer patients decide whether or not to undergo adjuvant RT. We developed and tested a DA for older women with stage I,ER/PR positive breast cancer considering adjuvant treatment post-lumpectomy and we examined its impact on treatment decision-making process.

Methods and Materials: A DA was developed and evaluated in three steps following the Ottawa Decision Aid Framework: 1) Needs assessment (N=16); 2) Pilot I, to examine the DA's acceptability (N=12); and 3) Pilot II, a pre-test post-test (N=38) with older women with ER/PR responsive breast cancer post-lumpectomy who were receiving adjuvant RT. Measures included questionnaires to assess patient's satisfaction with the DA, patients’ self-reported decisional conflict (DC), level of distress, treatment-related knowledge, and choice predisposition

Results: The DA is a booklet that details each adjuvant treatment option's benefits, risks and side-effects tailored to their clinical profile; includes a value clarification exercise; and steps to guide them towards their own treatment decision. All women felt the DA was helpful and informative. Compared with baseline scores, patients had a statistically significant (p < .05) reduction in DC (adjusted mean difference [AMD], −7.18; 95% confidence interval [CI], −13.50 to 12.59); increased clarity of the treatment benefits and risks (AMD, −10.86, CI, −20.33 to 21.49; and improved general treatment knowledge (AMD, 8.99, CI, 2.88 to 10.28) after using the DA. General trends were also reported in patient's choice predisposition scores suggesting potential differences in treatment decision after DA use. Discussion: This study provides evidence that this DA may be a helpful educational tool for this group of women. The quality of care for older breast cancer patients may be enhanced by using a tailored DA to help the patient be informed of their treatment options and to prepare for decision-making.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-03.
P5-17-01: Evaluation of Psychosocial Distress in Main Care-Givers of Patients with Metastatic Breast Cancer Who Receive Treatment in a Community Based Oncology Group Practice.
Authors: Weide R , Feiten S , Friesenhahn V , Heymanns J , Kleboth K , Mergenthaler U , Thomalla J , van Roye C , Köppler H
Published: June 2012

Introduction: It is well-known that people who care for patients with a metastatic carcinoma are exposed to an above-average level of psychosocial distress. No data are available concerning the distress of main care-givers of female patients with metastatic breast cancer, who are treated in a community based oncology group practice.

Methods: Standardized cross-sectional survey of main care-givers and patients with metastatic breast cancer who were treated in a community based oncology group practice in Germany between 04/2010-03/2011. Psychosocial distress of the patients and their main care-givers were evaluated using the German versions of the Distress Thermometer (DT) and the Problem List (PL). In addition anxiety and depression of the main care-givers were assessed using the Hospital Anxiety and Depression Scale (HADS-D).

Results: 83 female patients with a median age of 65 (41-93) were interviewed. 6% did not have a main care-giver, 7% indicated that they needed no support, 48% reported one main care-giver and 39% several. Partners (60%), children (47%), siblings (11%) and friends (10%) were the most important care-givers. 47% of patients preferred visiting the practice in companion with their care-givers. The patients’ median score on the DT was 5 (0-10), with 34% scoring above cut-off (> 5) for psychosocial distress. 52 main care-givers (61% male, 39% female) with a median age of 57.5 (41-86) were interviewed. The relationships to the patients were as follows: partners 62%, children 27%, mothers, siblings and friends each with 4%. The main care-givers themselves were supported by partners (54%), children (21%) friends (17%) and siblings (8%), 23% did not receive any support. The median score on the DT was 5 (0-10), with 44% scoring above cut-off (> 5) for psychosocial distress. According to the HADS-D 37% (cut-off ≥ 8) of the care-givers reported anxiety, with a mean score of 6.6 (0-14). 15% could be regarded as depressed (cut-off ≥ 8), with a mean score of 4.1 (0-15).

Conclusions: The main care-givers are distressed even more than the patients themselves. 37% of care-givers reported anxiety; depression can be observed too, but less frequently in 15%. Both issues should be addressed by healthcare professionals.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-17-01.
P5-19-04: Results of a Randomized Phase II Study Demonstrate Benefit of Platinum-Based Regimen in the First-Line Treatment of Triple Negative Breast Cancer (TNBC).
Authors: Fan Y , Xu BH , Yuan P , Wang JY , Ma F , Ding XY , Zhang P , Li Q , Cai RG
Published: June 2012

Background: It is supposed that triple negative breast cancer (TNBC) may be more sensitive to DNA damage agents such as platinum. This study was designed to compare platinum-based regimen (docetaxel plus cisplatin) with non-platinum-based regimen (docetaxel plus capecitabine) in the first-line treatment of advanced triple negative breast cancer patients.

Patients and Methods: This was a single-institution, randomized phase II clinical trial. Eligible TNBC women with first relapse or metastasis who had measurable disease were randomized (1:1) to receive either TP regimen (docetaxel 75mg/m2 plus cisplatin 75mg/m2 intravenous infusion day 1) or TX regimen (docetaxel 75mg/m2 intravenous infusion day 1 plus capecitabine 1000mg/m2 bid, two weeks on, one week off) every 3 weeks for up to 6 cycles, until disease progression, unacceptable toxicity or patient consent withdrawal. The primary endpoint was objective response rate (ORR) and secondary endpoints included progression free survival (PFS), overall survival (OS) and safety profile. To detect a difference of 0.35 in response rate between groups with a power of 80% and 2-sided significance level at 0.05, there should be at least 26 patients in each group. As of Jun 1st, 2011, 53 patients had been randomized and evaluated.

Results: After a median follow-up of 24 months, the results showed much higher response rate in TP group than TX group although the clinical benefit rate was not significantly different. PFS was more than doubled in TP group compared with TX group. Overall survival was also statistically improved. G3/4 vomiting was merely observed in 3 patients from TP group. On the contrary, only patients in TX group (5/26) reported G2/3 Hand-Foot Syndrome. No differences were found in hematological and other non-hematological toxicities.

Conclusions: Although it is a small sample size phase II study, it strongly suggested that cisplatin-contained TP regimen improved patient outcome, as measured by ORR, CBR, PFS and OS, compared with non-cisplatin-based TX regimen in the first-line treatment of advanced TNBC patients. This is the first prospective study to show superiority of cisplatin over capecitabine in TNBC. Together with additional ongoing clinical trials comparing platinum with other chemotherapeutic agents in various settings, the role of platinum in TNBC can be further elucidated.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-04.
P5-20-01: Patient Valuation of Reduced Risk of Side Effects during Treatment for Metastatic Breast Cancer.
Authors: Lalla D , McLaughlin T , Brammer M , Bramley T , Bare A , Carlton R
Published: June 2012

Background

Chemotherapy treatment for metastatic breast cancer (MBC) has shown significant benefits in survival for breast cancer patients. However, chemotherapy is associated with several side effects that have a significant impact on patients’ quality of life. The objective of this analysis was to quantify the value patients with MBC place on reduced risk of treatment side effects.

Methods: A willingness to pay (WTP) survey was developed to assess metastatic breast cancer patients’ willingness to pay for a reduction in the risk of breast cancer treatment side effects. The survey assessed patients’ WTP for a 25%, 50% and 100% reduction in the risk of all side effects. Patients were also asked to select the side effect they would pay the most to avoid. Additionally, the survey collected demographic information such as treatment regimen, age, race/ethnicity, region, employment status, and insurance type.

Results: The survey was completed by 202 metastatic breast cancer patients. Most survey respondents were white (94%), married (62%), and over the age of 51 (78%). Most patients were covered by private insurance (67%) or Medicare (24%). Of the 58% of respondents who remembered paying out of pocket for their last treatment, the average out of pocket payment was $459. Survey respondents were willing to pay an extra $1,886, $3,837 and $7,794 for a 25%, 50% and 100% reduction in the risk of all side effects, respectively. Hair loss (28%), pain (17%) and nausea (15%) were selected most often as the side effect respondents would pay the most to avoid.

Discussion: Chemotherapy for MBC is associated with several adverse events that patients would like to avoid or reduce such as hair loss, pain, nausea and neutropenia. This analysis demonstrates patients with MBC place a significant value on reducing the risk of side effects and are willing to pay 4.2 times for a treatment devoid of side effects as compared to a treatment with a 25% reduction in the risk of treatment side effects.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-20-01.
P5-23-04: Gonadotrophin-Releasing Hormone Analogues for Ovarian Function Preservation in Women with Premenopausal Breast Cancer Undergoing Adjuvant Chemotherapy: A Systematic Review and Meta-Analysis.
Authors: Cruz MRS , Motta E , Silva EMK , Bernardo SG , Atallah AN
Published: June 2012

Background: Breast cancer, the most common female malignancy, is also the most frequent tumor in women of reproductive age. Young women with breast cancer usually present adverse prognostic features and higher rates of recurrence when compared with their older counterparts. Adjuvant chemotherapy is usually recommended for this group of patients and premature ovarian failure (POF) is a potential complication.

Material and Methods: We conducted a systematic search in MEDLINE, EMBASE, Cochrane Systematic Reviews databases and ***ClinicalTrials.gov from their inception until June 2011. The search was conducted to include published peer-reviewed studies on the issue of fertility preservation in women with breast cancer undergoing adjuvant chemotherapy. The search terms were tailored individually for each database to include the following Medical Subject Headings (MeSH) and text words: gonadotropin releasing hormone, breast neoplasms, drug therapy, premature ovarian failure and fertility. No language restriction was applied. We also searched for additional studies by reviewing the reference lists of retrieved articles, and studies presented in abstract form were also located in this manner. The main outcomes were return of spontaneous menstruation, ovulation and pregnancy rate.

Results: We found 8 RCTs that met the inclusion criteria. Data were extracted from 3 RCTs. Data were only available for resumption of ovulation. There were no data available for markers of ovarian function, rate of ovulation and pregnancy. The rate of women with spontaneous menstruation demonstrated a statistically significant difference in favor of the use of GnRH-a (OR 3.11;95% CI, 2.04-472). Discussion: Use of GnRH concomitant to adjuvant chemotherapy in premenopausal breast cancer women aiming to reduce rates of POF has been subject of controversy during the last decade. Evidence from recently presented RCTs suggests there is a benefit of GnRH for ovarian function protection in this setting.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-23-04.
PD04-03: Sexual Dysfunction in Premenopausal Women with Breast Cancer: Prevalence and Severity.
Authors: Goldfarb SB , Dickler M , Patil S , Jia R , Sit L , Damast S , Carter J , Kaplan J , Hudis C , Basch E
Published: June 2012

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies. However, the prevalence and severity of sexual dysfunction in premenopausal women undergoing therapy for both local and metastatic disease is not well defined. This study was performed in order to understand the impact of contemporary breast cancer treatment on the prevalence and severity of sexual health in premenopausal women.

Methods: We developed a survey that includes a previously validated questionnaire, the Female Sexual Function Index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC), under an IRB waiver of consent.

Results: 372 consecutively approached premenopausal women with breast cancer of any stage, undergoing treatment were each queried once. The mean age was 47. 87% reported current or past hormonal treatment, and 86% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score <26, was reported by 75% of respondents with a mean score of 16.3. Among these women, 79% of patients considered their sexual symptoms to be bothersome, with 51% noting moderate or severe levels of bother (score >=5/10). In a multivariate analysis, metastatic disease, development of amenorrhea from cancer treatment, antidepressant use and poorer overall health were each significantly associated with worse FSFI scores. Lower FSFI scores were also significantly associated with worse health-related quality of life.

Conclusion: Sexual dysfunction is prevalent in premenopausal women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification and counseling.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-03.
PD05-05: Meta Analysis of Discordant HER2 Status in Matched Primary and Metastatic Breast Cancer.
Authors: Richter S , Zandvakili A
Published: June 2012

Background: The status of HER2 amplification in breast cancer is an important prognostic and predictive indicator. Only those tumors exhibiting HER2 overamplification are candidates for HER2 targeted therapy. It remains controversial how accurately HER2 status of primary tumors reflects HER2 status in distant metastases. Discordance between primary and metastatic tumors can impact significantly on patient management and suitability for HER2 targeted therapies in the setting of recurrent distant disease.

Methods: A literature search of the PubMed database was performed to identify all primary studies comparing HER2 status in matched primary and distant metastatic tumors between January 2005 and February 2011. Review and data extraction was performed by two independent reviewers. Eligible studies evaluated HER2 status by current ASCO guidelines. Studies comparing paired primary and axillary lymph nodes or synchronous primaries and metastases were excluded. Weighted pooled estimates were calculated.

Results: The original search strategy retrieved 1703 studies for which there were 62 eligible studies for full evaluation. Metastatic sites included bone, brain, lung and liver. Traztuzumab was received in three studies. Weighted summary estimate for negative to positive discordance was 23% (95% CI, 16.0-28%). Positive to negative discordance had a weighted summary estimate of 4% (95% CI, 0.0-6%).

Discussion: Meta analysis of studies adhering to ASCO guidelines for HER2 status determination revealed a significant rate of change to HER2 positive metastatic disease in HER2 unamplified primary breast cancers. This data suggests that nearly one quarter of patients may be denied the benefit of HER2 targeted therapy if HER2 primary status alone is used a the sole measure in determining therapeutic options upon distant recurrence.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-05.
PD05-06: Determination of HER2 Status with Analysis of Plasma DNA by Digital PCR in Patients with Metastatic Breast Cancer.
Authors: Graeser MK , Gevensleben H , Smith IE , Ashworth A , Turner NC
Published: June 2012

Background. A small proportion of originally HER2 negative primary breast cancers relapse with HER2 amplified disease. Identification of these cancers is important as these patients may benefit from HER2 targeting therapies. A proportion of free plasma DNA originates from the cancer, and accurate determination of HER2 copy number in plasma DNA has the potential to non-invasively determine HER2 status in patients with metastatic breast cancer. Digital PCR can differentiate small increases in DNA concentration with a much higher degree of accuracy than conventional quantitative PCR, and here we assess the potential of plasma DNA digital PCR to determine HER2 status.

Methods. We examined a cohort of 44 patients with metastatic breast cancer treated at the Royal Marsden Hospital who had received a median of 1.5 prior courses of chemotherapy for recurrent disease; 34 patients had ER positive and 9 HER2 positive (all 3+ positive HercepTest) disease as determined on biopsy of recurrent disease in 16 patients and original primary cancer in 28 patients. Following informed consent, plasma samples were taken, free plasma DNA was extracted and concentration determined with LINE1 quantitative PCR. We designed a custom HER2 copy number TaqMan MBG-probe (Applied Biosystems) and two chromosome 17 peri-centromeric control probes TUFMP1 and UBBP4, avoiding known SNPs and regions of normal copy number variation. Digital PCR was performed in 384 well format on a 7900HT Fast RT-PCR system, with copy number ratio determined using the Poisson distribution.

Results. HER2 Digital PCR assay was initially tested on DNA from 9 HER2 amplified cell lines. HER2/UPPB4 ratio was increased in 9/9 HER2 amplified cell lines, and HER2/TUFMP1 in 7/9 due to co-amplification of the 17q peri-centromeric DNA in 2 cell lines. Dilution experiments with SKBR3 DNA in non-amplified DNA demonstrated sensitivity down to ∼1% levels. We selected HER2/UBBP4 digital PCR for examination of patient samples. Plasma DNA Digital PCR HER2/UBBP4 ratios differed substantially between HER2 non-amplified (mean 1.047, SD 0.149, median 1.046, range 0.70−1.264), and HER2 amplified cancers (median 2.231, range 1.138−7.89, p<0.001). Digital PCR HER2 ratios had a high diagnostic accuracy with ROC curve AUC 0.967 (95% CI 0.585−0.997). With a threshold Digital PCR HER2 ratio of 1.3 the test had 100% specificity and 89% sensitivity, with negative predictive value 97%. The single miscalled HER2 amplified patient had a low tumour burden. Results of a test set using sequential probability ratio test analysis will be presented at the conference.

Conclusions: Plasma DNA Digital PCR accurately determined HER2 status in patients with metastatic breast cancer. Analyses of plasma DNA have the potential to replace biopsy sampling of metastatic disease to guided targeted therapy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-06.
PD06-10: Breast Cancer Patient Distress Associated with Difficulties Navigating the Costs Associated with Care: Results from a National Education Program.
Authors: Ahmed I , Gubin A , Champion L , Harvey A , Amsellem M
Published: June 2012

Compounding the stressors related with a diagnosis of breast cancer can be the associated direct and indirect costs of cancer care. To address this need, the Cancer Support Community (CSC) in 2009 developed an evidence-based, professionally-led national education workshop for cancer patients and caregivers entitled Frankly Speaking About Cancer: Coping with the Cost of Care. As part of this workshop, participants completed a survey describing their experiences coping with the cost of cancer care. To date, responses from 465 participants (representing 46 workshops) have been analyzed. Of those participants, 105 are women diagnosed with breast cancer. Though workshop participants were affected by a wide variety of cancer diagnoses, half of those with cancer attending the workshop (50%) were affected by breast cancer. No significant differences between breast cancer patients and individuals with other cancers were found. Analyses are based on responses from breast cancer patients only. Participants’ pre-workshop rating of their understanding about the financial aspects of their breast cancer care was low (m =2.8, s.d.=1.0) and was significantly less than their level of knowledge post-workshop (m =4.1, s.d.=0.7, p <.05).

Most attendees (72.8%) reported experiencing some degree of emotional distress from trying to manage cancer care costs, and nearly one-third of attendees (30.1%) reported significant distress. Most (64.8%) reported that their healthcare team did not discuss financial aspects of care with them. Of attendees whose team did discuss it with them, typically it was a social worker, physician, or nurse. Of those who had this discussion, only 34% reported that this information was actually useful to them. Not surprisingly then, attendees reported they have looked elsewhere for information about managing the costs of care, such as patient support organizations (40.2%), the Internet (43.5%), and other patients (41.3%).

A positive to arise from the workshop is that most participants (69.9%) reported the intention to discuss financial aspects of their care with their healthcare team based on what they had learned from the workshop. Intention to have this discussion with their healthcare team was both positively correlated with having experienced emotional distress about the cost of their care (r=.29, p <.05) as well as negatively correlated with their level of pre-workshop knowledge about financial issues in breast cancer care (r=-.28, p <.05).Taken together, these data highlight significant obstacles that individuals face in receiving meaningful information relevant to managing the costs associated with cancer care.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD06-10.