bluuebunny/crossref_metadata_2025 huggingface dataset:
P4-11-14: Number Needed To Treat (NNT) as a Measure of Incremental Drug Benefit: Denosumab vs. Zoledronic Acid for the Prevention of Skeletal Related Events (SREs) in Advanced Breast Cancer.
Authors: Dranitsaris G , Kaura S
Published: June 2012

Background

Intravenous zoledronic acid (ZOL) is the standard of care for the prevention of SREs in advanced breast cancer. However, monthly subcutaneous denosumab (Dmab) was recently approved in the US, as an alternative to ZOL based on the results of a large randomized trial which demonstrated a prolongation in median time to first SRE (HR = 0.82, p = 0.01) and a 5.8% (p = 0.01) absolute reduction in SREs in favour of Dmab over the 34 month study period. The challenge for clinicians and payers is how to reconcile the modest benefits of Dmab with the cost, which is approximately twice that of ZOL. NNT represents the number of patients that need to be treated with a new intervention in order to avoid one additional event, and is a widely accepted approach used to make sense of numerical results from clinical trials. In this analysis, the NNT approach was used to assess the incremental benefit of Dmab over ZOL for the prevention of SREs in advanced breast cancer.

Methods: The pivotal randomized trial for Dmab vs. ZOL in breast cancer (Stopeck, JCO 2010 & US PI 2010) was reviewed. As an alternative to ZOL, the NNT with Dmab to avoid any SRE at 12 and 34 months (trial end) was determined. NNT by type of SRE was also estimated. These consisted of pathologic fractures, radiation to bone, spinal cord compressions and surgery to bone. The calculated NNT represents the incremental benefit provided by Dmab above and beyond Zometa therapy.

Results: To avoid a single SRE after 12 months of treatment of continuous therapy with Dmab, approximately 36 patients need to be treated. To avoid a single fracture and radiation to bone, approximately 39 and 27 patients need to be treated with Dmab over a 34 month period. Dmab was unable to offer any incremental benefit over ZOL in terms of avoiding spinal cord compressions or surgery to bone after 34 months of treatment.

Discussion: The NNT approach is a simple and effective method to express the findings in a clinically meaningful way. In this analysis, the incremental benefit of Dmab would only be realized when a minimum of 36 patients are treated for 12 months. For the more severe skeletal-related events, in terms of clinical and economic burden to patients and society, such as spinal cord compression and surgery to bone, Dmab did not offer any incremental benefit over ZOL in terms of SRE avoidance. This marginal incremental benefit needs to be considered alongside the high cost of Dmab.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-14.
P4-11-18: Mammographic Surveillance in Atypical Hyperplasia of the Breast and Subsequent Development of Cancer. A Need for Long Term Follow Up.
Authors: Koron R , Sridharan U , Mitchell G , Holcombe C
Published: June 2012

Introduction Atypical hyperplasia of the breast is a known risk factor for breast cancer. Despite this risk there are no published guidelines on a recommended follow up regime for these patients.

Methods A retrospective study was carried out on 1920 core biopsy results within a major screening breast unit from 2001 to 2005. Patients who had a final diagnosis of Atypical Ductal Hyperplasia (ADH), Atypical Lobular Hyperplasia (ALH) and Lobular Carcinoma in Situ (LCIS) were included.

Information was extracted from multidisciplinary team meeting records, departmental data bases, pathology and radiology reports. Details of follow up and subsequent cancer diagnosis were noted.

Results 83 patients were diagnosed with ALH, ADH or LCIS from a core biopsy. The mean age was 54 years (range 40–85 years). Seventy six (91.6%) of these patients went on to have an excision biopsy. Sixty four (77.1%) women have received long term mammographic follow up ranging from 5 to 9 years to date. Nineteen patients did not receive mammographic surveillance. Of this group 2 patients with LCIS had bilateral risk reducing mastectomies and 2 patients died shortly after diagnosis with no evidence of breast cancer. Eight patients developed breast cancer 3 to 8 years after their initial diagnosis. Of these, four patients developed cancer in the same breast that atypia had been diagnosed in previously, and four in the contra lateral breast.

Conclusion 12.5 % of patients in the follow up group developed breast cancer within 8 years of diagnosis of atypical hyperplasia. A review of the literature suggests that in view of the increased risk of subsequent breast cancer in this group of women long term follow up is required. On the basis of these findings we recommend that all patients diagnosed with ALH, ADH or LCIS should be entered into an 18 monthly mammogram surveillance programme for 15 years.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-18.
P4-11-22: Familial History of Cancer among Breast Cancer Women under 36 yr. in Rio De Janeiro, Brazil.
Authors: Koifman S , Ortega GPJ , Koifman RJ
Published: June 2012

Background. Antecedents of familial history of cancer (FHC) have been reported as an important feature observed among young women with breast cancer (BC).

Objective. To explore the distribution of FHC in a sample of young women with BC in Brazil.

Methods. Antecedents of FHC were obtained by a face to face interview carried out with 224 BC cases 20–35 yr., and 246 age-frequency matched controls, enrolled in a hospital-based case control study carried out along 1996–2006 in Rio de Janeiro, Brazil. Unconditional logistic regression was performed and BC odds ratios adjusted for age and education (adj. OR) were obtained according to FHC characteristics (parenthood degree, age of diagnosis and amount of relatives with cancer).

Results. BC antecedents among 1 st degree relatives was 5.4% among BC cases and 1.2% of controls (p=0.01). The adj. OR for BC among 1st degree relatives was 4.3, 95% CI 1.2−15.8. Comparatively to families without BC antecedents, an adj. OR =2.4, 95% CI 1.4−4.1 was observed for those with 1 reported BC case, and an adj. OR = 3.7, 95% CI 1.0–14.0 for those with 2 or more BC cases (p trend =0.0002). A similar trend was verified according to all other cancer sites (p-trend < 0.0001). The reported median age of BC diagnosis in the 1st generation (proband grand-mothers) was 76 yr., being 45 yr. at the 2nd generation (proband mothers), and 38,4 yr. at the 3rd (proband sisters). A similar trend along generations was also verified for other cancer sites among case relatives, respectively, 69 yr., 58 yr. ***, and 45 yr. The mean age of diagnosis among the cases offspring was 6.7 yr. (standard deviation, SD = 0.6) and 12.0 yr. (SD = 1.4) among the controls descents (p< 0.01). Brain cancer reported among case relatives was 6.0 fold higher than among control relatives (3.7 fold higher for ovarian cancer, and 3.2 higher for skin cancer).

Discussion. The observed results reveal that cancer risks among relatives of young women with BC are either higher for BC or other selected cancer sites. The observed decline along successive generations on the age at diagnosis of BC and other tumors is suggestive of recent genetic-environmental interaction in the studied sample of young women with BC in Brazil.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-22.
P4-14-05: Chemotherapy-Induced Alopecia, Body Image and Psychological Distress in Women with Breast Cancer: A Prospective Study.
Authors: Choi E-K , Kim I-R , Nam S-J , Lee J , Yang J , Lee S-K , Noh D-Y , Han W , Cho J
Published: June 2012

Purpose: While chemotherapy-induced alopecia (CIA) is known to be associated with lower quality of life, the longitudinal effect of alopecia on body image and distress in unknown. This study examined effect of CIA on body image and psychological distress during active breast cancer treatment.

Patients and Methods

Between July and Dec 2010, we recruited patients with non-metastatic breast cancer who were expected to receive adjuvant chemotherapy (N=411) from two cancer hospitals in Seoul, Korea. After excluding 15 patients with recurrence and 65 patients lost to follow-up, the present analysis is based on 331 patients (80.5%). Participants completed questionnaires on body image, quality of life, alopecia distress at enrollment (before surgery), before chemotherapy (2 weeks post surgery), during chemotherapy (3 months post surgery), and after chemotherapy (6 months post surgery). Body image and quality of life were assessed by the EORTC QoL Questionnaire BR23. Alopecia distress was assessed by the Alopecia Distress Scale, which evaluated distress in 4 domains: physical, emotional, daily activity, and relationship.

Results: The mean age of the participants was 46.4 (SD 7.91) year. 44.9% and 37.6% of them had stage I and II breast cancer, respectively. 83.0% of the patients had lumpectomy, and 70.6% and 85.9% had chemotherapy and radiotherapy, respectively. Patients who experienced alopecia had a significantly more negative body image and higher distress compared to those who did not experience alopecia. Body image rapidly decreased at 3 months post surgery coinciding with alopecia, and its effects lasted until 6 months post surgery. Moreover, there was a highly statistically significant association between more negative body image and higher alopecia distress after adjusting for other socio-demographic and clinical characteristics. The patterns and changes in body image and distress comparing patients with and without alopecia are reported in Table 1.

Discussion: Health professionals need to develop clinical pathways and education programs to help women with breast cancer manage alopecia distress and negative body image during active treatment.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-14-05.
P4-16-06: Expression Patterns of Receptor Activator of Nuclear Factor-kB (RANK) and Src in a Series of Primary Breast Tumors (BT) and Bone Metastases (BM) in Patients (pts) with Metastatic Breast Cancer (MBC).
Authors: Gucalp A , Comen E , Redana S , Evangelista L , Giri DD , Zhang XH , Patil S , Akram M , Norton L , Hudis CA , Fornier MN
Published: June 2012

Background

BM develops in 65–70% of pts with MBC. RANK and its ligand (RANK-L) can be critical in the development and progression of BM. Src overexpression and deregulation occurs in many solid tumors but it has not been fully characterized although an association between Src activity defined by a gene expression signature and BM particularly in ER+ pts has been described. (Zhang XH et al. Cancer Cell. 2009) Our goal was to elucidate the relationship between Src and RANK expression in BT and BM in relation to estrogen-/progesterone-receptor (ER/PR)/HER2 expression and tumor histology (invasive ductal carcinoma (IDC) vs invasive lobular carcinoma (ILC)).

Methods: Immunohistochemistry (IHC) for RANK (R&D Systems clone 80707) and Src (Cell Applications Inc. Phospho Tyr-416) protein expression was performed on archived paraffin embedded BT and BM. Scoring: 0=negative, 1+=weak, 2+=intermediate, 3+=strong and the percent of positive tumor cells; RANK+ = 2–3+, > 1% of cells; Src+ = 1–3+; > 1% of cells. Associations between RANK/Src expression and tumor characteristics were assessed using the chi-square test or McNemar's test for pairs, as appropriate.

Results: From the MSKCC database, using an IRB-approved waiver of consent, we identified 54 pts with MBC who underwent surgical biopsy of a metastatic bone lesion at our center between 2005–2010, and had tissue available for further testing. 17 corresponding BT samples were identified. At the time of diagnosis, 43 (79.5%) primary tumors were ER or PR (+); 6 (11%) were HER2+; 41 (76%) were invasive ductal carcinoma. 87% of BM expressed RANK and 44% expressed Src. (Table 1) No significant correlation between RANK or Src expression in BM and ER/PR/HER2 status of BT was observed. A significant correlation between RANK expression and BT histology was observed, (p=0.0016): 93% of IDC were RANK (+), in comparison to 50% of invasive lobular carcinomas. RANK expression was not significantly different between primary tumor and metastatic bone samples (p=0.99). There was a borderline significant difference in Src expression between primary and metastatic site (p=.06).

Conclusions: In our cohort, no correlation between RANK or Src by IHC and ER/PR/HER2 was identified but RANK expression was more common in IDC than ILC. Fidelity was high for RANK between primary and metastatic lesions while Src expression may possibly vary.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-06.
P4-17-10: Insights into Mechanisms Involved in the Accumulation of Nanovectors within the Breast Cancer Brain Metastasis.
Authors: Yokoi K , Xuewu L , Alexander JF , Fidler IJ , Mauro F , Biana G
Published: June 2012

Systemic chemotherapy for brain metastasis of breast cancer (BMBC) is considered to be inefficient. It is widely accepted in the literature that blood-brain-barrier (BBB) is responsible for clinical failures with the conventional chemotherapy. We hypothesized that nanovectors, therapeutic carriers with submicron dimensions, can be delivered to the brain tissue through a different pathway than molecular therapeutics. The objective of this study was to examine the accumulation of various intravenously injected nanovectors into the brain metastasis of breast and other cancers loci and to explore possible mechanisms involved.

Both human (MDAMB231) and mouse (4T1) breast cancer brain metastasis were evaluated. We also tested lung (3LL) and colon (CT26) originated cancers. Orthotopic brain tumors were produced either by intracarotid injection or stereotactic brain injection of cancer cells. When the animals became moribund, they were injected intravenously with one of the following nanovectors including fluorescently labeled PEGylated (100nm) and non-PEGylated (100nm, 250nm, 500nm) liposomes, disc-shape silicon particles (600, 1000nm in diameter). The accumulation of the nanovectors was compared to an unencapsulated fluorescent molecule. The accumulation of the nanovectors in the brain tumor tissue was evaluated through live animal imaging (IVIS) and immunohistochemical analysis. Immunohistochemical staining of endothelial cells and basal membrane markers was performed to determine the integrity of the tumor associated vasculature and the co-localization of the fluorescent nanovectors/molecules with tumor associated vasculature.

Interestingly, we have found that brain metastasis of different tumors (originated form breast, lung and colon cancers) possess dissimilar accumulation profiles for intravenously administered nanovectors. For example when comparing various tumor origins, 4T1 breast cancer originated brain tumors enabled the highest accumulation of the nanovectors as compared to CT26 and 3LL. On the other hand, free molecule accumulated into the 4T1 brain metastasis model to a much lower extend than in nanovector. Finally, the observed brain distribution of nanovectors corresponded well with impairment in vascular endothelium and basal membrane integrity shown in immunohistochemical analysis.

The results of our study point toward a possibility to treat specific patients with impaired BBB function with nanovector encapsulated chemotherapeutics based on the fact that their transport, accumulation and retention in the brain tissue are governed by different biological mechanisms, such as Enhanced Permeation and Retention (EPR) effect. These studies indicate that it is possible to cross the blood brain barrier, thus giving hope to patients with brain metastasis.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-10.
P4-19-01: Male Breast Cancer According to Tumor Subtype and Race: A California Cancer Registry (CCR)-Population Based Study.
Authors: Chavez-MacGregor M , Clarke CA , Lichtensztajn DY , Hortobagyi GN , Giordano SH
Published: June 2012

Background

Breast cancer in men is a rare disease and accounts for 0.6% of all breast cancer cases. Prior reports suggest that male breast cancer typically has a ductal histology and is more likely than cancers of the female breast to express estrogen and progesterone receptors (ER and PR). To our knowledge, there are no population-based estimates of the rates of Her-2 positive breast cancer or of the distribution of breast cancer subtypes in male patients. The categorization of breast cancers according to tumor subtype has important implications in the prognosis and in the management of breast cancer patients. We explored the tumor subtype distribution by race/ethnicity in the large, ethnically diverse population of California.

Methods: Retrospective study using the CCR. Participants included all male breast cancer patients diagnosed with invasive breast cancer between 2005–2009 with known ER, PR and Her2neu status. Among the patients with hormone receptor positive (HR+) tumors, survival analysis using Kaplan-Meier method was used. Differences in probability of survival between groups were compared using logrank test.

Results: Six-hundred and seven patients were included. Median age at diagnosis was 68 years. Ductal histology was present in 84.7% (n=514) of the cases, 51.6% (n=313) of all the tumors were classified as grade II. Four hundred and ninety four (81.4%) patients had HR+ tumors, defined as ER+ and/or PR+ and Her2neu negative. Ninety (14.8%) had Her2neu positive, and 23 (3.8%) had triple receptor negative tumors (TN). The majority of patients were white (71%), 11% were Hispanic, 7.6% black and 10.4% were Asian/Pacific Islander/other. The breast cancer tumor subtype varied significantly across races/ethnicities (p<.0001). Among non-Hispanic Whites, 82.6% had HR+, 14.6% had Her-2+, and 2.8% had TN breast cancer. For Blacks and Hispanics the distributions were 73.9% HR+, 17.4% Her-2+, 8.7% TN and 77.6%, 16.4%, 6.0% respectively. Among HR+ patients, blacks and Hispanics were less likely to have PR+ tumors compared to whites. The rate of ER+PR- was 6.3% among whites, 19.6% among blacks and 16.4% among Hispanics (p<0.001). A survival analysis among HR+ patients showed significant differences according to race (p=0.018) and stage (p<0.001), with Black patients and patients with higher stage disease having poorer outcomes.

Conclusions: In this large cohort of male breast cancer patients, the distribution of tumor subtype was different than what has been reported in females. Among males, differences in tumor subtype exist among different racial/ethnic groups. Blacks were more likely to have triple receptor negative tumors and more likely to have ER+/PR- tumors than white patients. Among HR+ patients, blacks experience the worse survival.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-19-01.
P4-19-03: Physical and Psychological Sequelae of Breast Cancer in Men.
Authors: Ruddy KJ , Giobbie-Hurder A , Giordano SH , Goldfarb S , Kereakoglow S , Winer EP , Partridge AH
Published: June 2012

Introduction: Little is known about the physical and emotional health of men with breast cancer. Information is also lacking regarding whether their informational and supportive care needs are being met regarding fertility and genetic concerns.

Methods: In an online pilot study recruiting participants through three websites focused on male breast cancer, www.outoftheshadowofpink.com, www.malebreastcancer.org, and www.malebreastcancer.ca, we surveyed men with breast cancer about their attitudes, symptoms, experiences, and health perceptions. We measured anxiety and depression using the Hospitalized Anxiety and Depression Scale (HADS), health-related quality of life (QOL) using Functional Assessment of Cancer Therapy-Breast (FACT-B), and hormonal and sexual symptoms using the Expanded Prostate Cancer Index Composite (EPIC) Hormonal and Sexual Scales. We assessed select toxicities from therapy and history of genetic and fertility counseling.

Results: Forty-two men responded to this online survey at least in part.

Conclusions: Men with breast cancer experience substantial symptoms in follow-up. Sexual functioning, in particular, may be impaired (in men without cancer, mean EPIC Sexual Score is 61.4 with SD 23.6). Hormonal symptoms are also prevalent (in men without cancer, mean EPIC Hormonal Score is 91.7 with SD 9.7). We plan to use data from this pilot study to inform a larger study and develop targeted interventions to improve sexual functioning and reduce symptoms in male breast cancer survivors.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-19-03.
P5-02-01: ErbB4 Ectodomain as a Biomarker and a Potential Therapeutic Target for Breast Cancer.
Authors: Hollmen M , Liu P , Wildiers H , Reinvall I , Vandorpe T , Smeets A , Deraedt K , Vahlberg T , Joensuu H , Leahy D , Schoffski P , Elenius K
Published: June 2012

ErbB4 function is controversial in breast cancer and influenced by alternative splicing of the ERBB4 gene. Here we evaluated the cleavable ErbB4 JM-a isoform as a potential drug target and biomarker. To address ErbB4 cleavage in breast cancer tissues in vivo, extracellular and intracellular cleavage products of ErbB4 were assessed by ELISA and immunohistochemistry using matched serum and tissue samples from a series of 243 breast cancer patients. Elevated serum ectodomain level (≥40 ng/mL) and nuclear immunoreactivity were present in 21% and 52% of the patients, respectively. An elevated serum ErbB4 ectodomain concentration was not associated with tumor nuclear immunoreactivity, but was significantly associated with the premenopausal status at diagnosis (P = 0.04). Estradiol also enhanced ErbB4 cleavage and ErbB4 cleaving enzyme activity in vitro, supporting a role for estrogen signaling in regulation of ErbB4 cleavage. Selective targeting of the cleavable ErbB4 JM-a in human breast cancer cells with an ErbB4 isoform-specific mAb 1479 inhibited ErbB4 cleavage and reduced tumor formation in a mouse xenograft model. Consistent with blocking of ErbB4 cleavage, mutagenesis studies and the 3.4 Å X-ray crystal structure of a complex of the ErbB4 extracellular region and the 1479 Fab localized the binding site of mAb 1479 on ErbB4 to a region on subdomain IV encompassing JM-a-specific residues. These data demonstrate that ErbB4 is cleaved in a subset of breast cancer patients, and suggest that the mechanisms by which mAb 1479 suppresses breast cancer cell growth involves inhibition of ErbB4 cleavage. Serum ErbB4 ectodomain concentration could be used as a biomarker to monitor the activity of compounds, such as mAb 1479, that target ErbB4 cleavage.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-01.
P5-02-05: Real-Time Subcellular Imaging of Breast Cancer Cell Attachment in Blood Vessels Using GFP-Labeled Paxillin in Live Mice.
Authors: Suetsugu A , Digman M , Gratton E , Moriwaki H , Saji S , Bouvet M , Hoffman RM
Published: June 2012

Background: Paxillin is involved in the assembly of focal adhesions. We wish to visualize paxillin behavior in breast cancer cells in vivo, as well as in vitro.

Materials and Methods: Dual-photon confocal microscopy was used to image paxillin behavior by linking it to GFP. MDA-MB-231 human breast cancer cells expressing paxillin-GFP were imaged in vitro and in vivo adhering and trafficking in blood vessels in mice. 106 paxillin-GFP expressing breast cancer cells were injected in the epigastric cranialis vein.

Results: In vitro, round breast cancer cells had greater paxillin movement than stretched cancer cells as seen by fluorescence imaging. Paxillin-GFP breast cancer cells in the epigastric cranialis vein were initially rounded and had GFP-expressing protrusions. At later timepoints, many paxillin-GFP-expressing breast cancer cells stretched. The breast cancer cells then extravasated and subsequently grew around the outer surface of the blood vessel after one week. Two weeks after injection, paxillin-GFP expressing breast cancer cells were imaged migrating along the vessel wall. Most of the paxillin-GFP expressing breast cancer cells were stretched and were not mobile. With anti-VEGF treatment, paxillin was observed in round structures within the cells rather than stretched structures and paxillin movement within the cell was arrested.

Discussion: These results demonstrate that breast cancer cells brightly expressing paxillin-GFP and two-photon confocal microscopy can allow the visualization of the behavior of paxillin within breast cancer cells during adhesion and migration along the walls of blood vessels, as well as during anti-angiogenesis therapy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-05.
P5-03-02: Aurora A Is Closely Linked to an Aggressive Phenotype of Breast Cancer.
Authors: Yamamoto Y , Ibusuki M , Murakami K , Iwase H
Published: June 2012

(Purpose) Aurora A, a mitotic serine/threonine kinase, is involved in important process of mitotic progression. The aim of this study is to clarify characteristics of breast cancer with Aurora A expression. (Methods) We examined, by immunohistochemical analysis, the expression of Aurora A in primary invasive breast cancer. We also investigated the correlation between expression of Aurora A and clinicopathological and biological factors. In addition, we studied the prognostic value of Aurora A in breast cancer.

(Results) In 215 cases of invasive cancer examined, Aurora A was mainly identified in tumor nuclei. Aurora A expression was detected in 67 (31.2%) cases. Expression of Aurora A was correlated with tumor size (p=0.002), lymph node metastasis (p=0.002), tumor stage (p=0.04) and histological grade (p=0.0031). Aurora A expression was also associated with hormone receptor negativity (p=0.0001), and increased levels of HER2 (p<0.0028), Ki67 (p<0.0001), HIF-1alpha (p<0.0001), VEGF (p=0.007), COX-2 (p=0.002) and p53 (p<0.0001). Patients who had increased Aurora A levels in their tumor showed shorter disease-free survival (DFS) (p<0.0001) and overall survival (OS) (p=0.0002) than those lacking Aurora A in univariate analysis. However, in multivariate analysis of DFS and OS, Aurora A was not identified an independent prognostic factor.

(Conclusion) Aurora A expression was significantly correlated with tumor burden, poorly differentiation, negativity of hormone receptors, tumor cell proliferation, and tumor angiogenesis. These findings suggest that Aurora A was closely related with an aggressive phenotype in breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-03-02.
P5-05-03: The Effect of Breastfeeding on Molecular Characteristics of Invasive Breast Cancer.
Authors: Ellsworth RE , Valente AL , Kane JL , Shriver CD
Published: June 2012

INTRODUCTION: Breastfeeding has been associated with an overall decreased risk of developing breast cancer and the protective effect of breastfeeding has been associated with decreased risk of triple negative and estrogen-responsive breast cancer. Although the mechanism by which breastfeeding provides a protective effect is not well-defined, physical changes in the mammary epithelium reflecting maximal differentiation, may be involved.

METHODS: The database of the Clinical Breast Care Project was queried to identify all patients born between 1946 and 1964 (“baby boomers”) with invasive breast cancer who had given birth to at least one living child. Clinicopathologic characteristics were compared between patients who breastfed for at least six cumulative months and those who never breastfed using chi-square and Fisher's exact tests. RNA was isolated after laser-microdissection of 24 pairs of breastfeeding and non-breastfeeding tumors matched by stage, subtype and grade. Gene expression data was generated using HG U133A 2.0 microarrays and analyzed using the Partek Genomics Suite using a FDR<0.05, 2-fold expression difference to define significance.

RESULTS: Of the 1,008 parous women with invasive breast cancer in the database, 325 (33%) breastfed at least 6 months, 165 (16%) breastfeed less than 6 months, and 518 (51%) never breastfed. Women who breastfed <6 months were not included in additional analyses. Age at menarche and first birth and number of children did not differ between groups; age at diagnosis was significantly (P<0.0001) lower (54.5 years) in women who breastfed compared to those who did not (61.0 years). No differences were detected between patients who breastfed and those who did not for ethnicity or for any tumor characteristics, including tumor stage, grade or size, hormone, HER2 or lymph node status, or subtype. At the molecular level, however, 21 probes representing 19 genes were differentially expressed between women who breastfed and those who did not. Eleven genes, including HAPLN1, had significantly higher and 8 genes, including LGALS7, had significantly lower expression in tumors from women who did not breastfeed.

CONCLUSIONS: Despite the matching of tumor samples, and lack of differences in pathological characteristics between women who breastfed ≥6 months and those who did not breastfeed, differentially expressed genes were identified between tumors from the two groups. Many of the differentially expressed genes have been associated with prognosis, especially in ER negative breast tumors. These data suggest that breastfeeding does alter the underlying molecular characteristics of invasive breast tumors, and may reflect alterations in exposure to estrogen levels during breastfeeding.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-03.
P5-05-05: Human Papiloma Virus Identification in Intraductal Papilloma and Breast Cancer Using Broad-Spectrum Primers.
Authors: Balci FL , Bender O , Coskun F , Duzgun AP , Saylam B , Yuney E , Rota S , Fidan I , Feldman S , Soran A
Published: June 2012

Background

There is limited data about Human Papiloma Virus (HPV) presence in intraductal papilloma, and there are some conflicted studies about the effects of HPVs on breast cancer. Most of these studies have methodological pitfalls as well. We conducted a retrospective paraffin block study to understand the presence of HPV in papilloma and cancer tissues with broad-spectrum primers.

Methods: Twenty seven intraductal papilloma and 18 breast cancer patients’ paraffin blocks were obtained from the patients who underwent ductoscopy aided papillomectomy or mastectomy. In totally 87 histopathological samples, HPV-DNA were identified by real time PCR and broad-spectrum genotyping was performed by in situ hybridization. The cancer patients were evaluated according to the status of Estrojen Reseptor (ER), Progesteron Reseptor (PR) and ErbB-2 positivity.

Results: The mean age±SD was 49±16 in papilloma and 52±14 in breast cancer patients. We found that 29.6% (8 of 27) of intraductal papillomas and 44.4% (8 of 18) of breast cancer paraffin blocks had HPV-DNA positivity by PCR in situ hybridization with broad spectrum primers. Fifty percent (4 of 8) of HPV-DNA positive papillomas had only type 11; in one, only type 6; in one, mixture of type 6,11; in one, mixture of type 11, 39; and in one, mixture of type 11, 39, 82 was detected. Breast cancer lesions had only type 11 of HPV-DNA positivity in 62.5% (5 of 8) of cases; in one, mixture of type11, 39; in one, mixture of type 11, 82; in one, mixture of type 6, 11, 39 was detected. In seven HPV-DNA positive cancer patients, ER/PR and/or ErbB-2 was positive, but it was only positive in one triple negative patient.

Conclusion: HPVs may have a role in developing papilloma and breast cancer. Validation of HPVs role in the etiology of breast cancer/papilloma, require further studies to understand whether the HPVs are episomal or integrated during the tumorigenesis.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-05.
P5-07-04: Is a-L-Fucose Overexpressed on Cells of Aggressive Human Breast Cancers?
Authors: Listinsky JJ , Siegal GP , Listinsky CM
Published: June 2012

Enzymatic removal of a-L-fucose (fucose) was shown over 20 years ago to abolish metastases in vivo in a rat model of mammary adenocarcinoma [J Cell Biochem 1988; 37: 49–59]. Since that time, evidence has accumulated to indicate that fucose is a functional effector in human breast cancer; essential for construction of the invasive and metastatic phenotypes. In light of these findings, the role of fucose in aggressive breast cancers is worthy of further investigation.

Our group has modified the method of Wright et al. in order to selectively remove cell surface fucose from viable human breast cancer cells in vitro. In our experience, a 30 min incubation of breast cancer cells with α-L-fucosidase (3.2.1.51) leads to a loss of transformative abilities including decreased cancer cell adhesion to select extracellular matrix components, decreased invasion into complex extracellular matrices, decreased binding by relevant antibodies and lectins, and decreased adhesion of cells (rolling) to model endothelium under shear stress flow conditions.

From this work we postulated that decisive differences in phenotypic and functional properties between treated and control human breast cancer cells should be obtainable with currently available models of aggressive disease. To that end, we and others have subsequently shown that human breast cancer cells express cell surface CD44 which carries fucosylated ligands and that its’ defucosylation altered its’ malignant phenotype.. Based on these precedents, it is reasonable to hypothesize that CD44-enriched breast cancer stem cell populations require fucose in order to exert their aggressive behavior. Assays to assess the role of fucose in these stem cells are apparent and include a battery of tests involving stem cell invasion into extracellular matrices, cell binding of antibodies or fucolectins, stem cell aggregation into spheroids, colony formation in soft agar, assessment of stem cell rolling/adhesion to endothelial cells or purified E-selectin under both static or physiological flow conditions and the ability to initiate tumors upon inoculation into animal models.

We believe that new insights into aggressive breast cancer cell behaviors can be gained through the depletion of cell surface fucose from breast cancer cells. Knowledge gained from these studies should yield new insights when using current models of human breast cancer in vitro and in vivo.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-04.
P5-11-05: Measurement of Neoadjuvant Chemotherapy Tumor Response in Locally Advanced Breast Cancer by Three Methodologies. Correlation with Overall Survival.
Authors: Garcia-Saenz JA , Romero A , Lopez Garcia-Asenjo JA , Roman JM , Moreno A , Fuentes M , Furio V , Pelayo A , Diaz-Rubio E , Caldes T , Martin M
Published: June 2012

Background

Measurement of residual disease following neoadjuvant chemotherapy that accurate predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for new drugs efficacy evaluation. Several methods to assess neoadjuvant chemotherapy tumor response have been described. However, to our knowledge, agreement between methods and correlation with survival in independent prospective cohorts has not been reported.

Patients & Methods: In this study we report neoadjuvant chemotherapy tumor response and survival in 151 consecutive LABC patients, included in a neoadjuvant clinical trial (http://www.clinicaltrials.gov; NCT00123929). Patients were randomized to either neoadjuvant docetaxel 100 mg/m2 every 21 days or neoadjuvant doxorubicin 75mg/m2, every 21 days, for 4 cycles. Following surgery, response was established according to three methodologies: the measurement of residual breast cancer burden (RBC) as described by Symman's (Symmans WF et al. J Clin Oncol. 2007;25:4414–22), Miller and Payne classification (Ogston KN et al. Breast. 2003;12:320–7) and RECIST criteria. Regarding to Symmans classification we have evaluate both RBC index, as a continuous variable, and RBC classes as a categorical variable (RBC-0,I,II,III). Kappa Cohen's coefficient (K) was used to test agreement between methods. We assessed the correlation between treatment outcome and overall survival (OS) by calculating the Harrell's C- statistic.

Results: Median of follow up was 51.9 months. All three methods showed a moderate capacity to classify patients according to OS. The C-statistic to predict OS was 0.76 (IC: 0.67- 0.84) for RBC index and 0.71 (IC: 0.64−0.78) for RBC classes, 0.68 (IC: 0.58−0.78) for RECIST criteria and 0.69 (0.60−0.78) for Miller and Payne classification. Interesting, we did not encountered any death events within RCB-0 class. No significant differences were found between C-statistic when patients were stratified according to therapy. In order to assess the agreement between techniques, we grouped categories 1 and 2 of Miller and Payne classification in 1 category. The agreement between Miller and Payne classification and Symmans method was very high (K=0.87). In contrast, we found a moderate-fair agreement between Miller and Payne classification and RECIST criteria (K=0.46) and Symmans method and RECIST criteria (K=0.27).

Conclusion: All three methods predicted fairly well OS. RCB-0 identified the best outcome group. The agreement between methodologies based in pathology analyses was very high. However, the agreement falls off when these methodologies were compared with RECIST criteria.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-05.
P5-11-07: Receptor Concordance in Triple-Negative Breast Cancer (TNBC) Recurrences.
Authors: Killian ME , De Los Santos JF , Forero-Torres A , Krontiras H
Published: June 2012

Background: The phenotype of TNBC is defined by absence of estrogen (ER) and progesterone receptors (PR) and lack of amplification of the HER2 oncogene. It is an aggressive form of breast cancer, and despite sensitivity to contemporary chemotherapy, TNBC have a poorer prognosis than ER positive phenotypes, marked by early relapses. This study examines the concordance of receptor status in recurrences among patients with TNBC. Methods: After obtaining IRB approval, we identified patients with triple negative breast cancer treated at the University of Alabama at Birmingham between 1998 and 2010. Patient and tumor characteristics and disease status were recorded. Patients with ER, PR, or HER2 (3+) positivity on immunohistochemistry (IHC), or HER2 amplification by fluorescence in situ hybridization were excluded. Data regarding the receptor status of the recurrence, if known, was documented. Results: Five hundred and two women with TNBC were diagnosed at our institution between 1998 and 2010. Of these patients, 95/502 (19%) had recurrences. Twenty-seven (28%) were local, 18 (19%) were regional, 35 (37%) were distant, and 15 (16%) were both local-regional and distant. These women ranged in age from 33 to 84 years of age. Of the women with a recurrence, 78/95 (82%) had a biopsy confirming breast cancer recurrence. Of those biopsied, 33/78 (42%) had receptor studies performed, and of these, 30 included data for estrogen, progesterone and HER2 receptors. The remaining 3 had only IHC for estrogen receptors performed. Twenty-two/thirty (73%) had concordance on their biopsy with their initial TNBC status, whereas 8/30 (27%) women developed a pathologically discordant recurrence. Conclusion: In this single institution study of TNBC patients, approximately one quarter of patients developed a pathologically discordant distant recurrence noted at biopsy. It is unclear whether patients experiencing a pathologically discordant recurrence differ in prognosis from those with concordant recurrences. Further study is necessary to evaluate this and determine whether routine biopsy based on pathologic discordance rates and outcomes are warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-07.
P5-11-13: Rates of Upgrade to Malignancy for 271 Cases of Atypical Columnar Cell Hyperplasia Diagnosed by Breast Core Biopsy.
Authors: Peres A , Barranger E , Becette V , Boudinet A , Guinebretiere J-M , Cherel P
Published: June 2012

Purpose: Atypical columnar cell hyperplasia (ACCH) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ (CIS) and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance.

Methods: We retrospectively reviewed the data for 271 ACCH cases among 5555 breast core biopsies obtained over a 7-year period (Jan. 2003 — Jan. 2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate.

Results: The 271 ACCH comprised 128 cases of pure ACCH, 135 cases of ACCH + atypical ductal hyperplasia, and 8 cases of ACCH + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis.

Conclusion: The presence of ACCH at biopsy warrants surgery.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-13.
P5-11-14: Flat Epithelial Atypia of the Breast: A Single Institution Experience.
Authors: Joh JE , Acs G , Kiluk JV , Laronga C , Khakpour N , Lee MC
Published: June 2012

Background: Flat epithelial atypia of the breast is a relatively new entity of unknown significance. Our objective is to evaluate our surgical experience with this diagnosis.

Methods: A single institution database of breast patients from 2005–2010 was used to identify women who were diagnosed with flat epithelial atypia on core biopsy and subsequently underwent surgical excision. Patient data regarding history, type and reason for biopsy, and associated pathology was collected. Individuals diagnosed with flat epithelia atypia and cancer on core biopsies in the same breast were excluded.

Results: There were 52 patients who underwent surgical excision for the primary diagnosis of flat epithelial atypia. There were 3 (6%) patients with a personal history of breast cancer, 14 (27%) patients with a family history of breast cancer, and 11 (21%) patients with a concurrent new diagnosis of breast cancer in the contralateral breast. Core biopsy was recommended in most (81%) cases because of suspicious calcifications on mammography. Twenty-eight (54%) patients were found to have flat epithelial atypia associated with other atypical breast hyperplasia and 24 (46%) had flat epithelial atypia as the most significant lesion on core biopsy. In 8 (15%) patients, there was a sonographic correlate that was biopsied; 5 had only flat epithelial atypia and 3 had flat epithelial atypia associated with other atypical hyperplasia. Of the 52 patients there were 4 (8%) patients who upstaged to ductal carcinoma in-situ on surgical excision. There were no cases of invasive carcinoma. All ductal carcinoma in-situ cases were associated with other atypical breast hyperplasia, not flat epithelial atypia alone.

Conclusion: Though flat epithelial atypia may be associated with an increased risk of breast cancer, surgical excision of pure flat epithelial atypia may not be necessary. Larger studies are needed to corroborate these findings.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-14.
P5-13-06: Lipidomic Profile Predicts Pathologic Complete Response to Neoadjuvant Weekly Paclitaxel Treatment.
Authors: Facina G , Calux NMCT , Silva MFR , Bonetti TCS , Nazario ACP , Silva IDCG
Published: June 2012

BACKGROUND: Neoadjuvant chemotherapy is one of the main strategies for patients with advanced breast cancer. The taxane paclitaxel have an important role in inhibiting microtubule polymerization and this mechanism prevents cells from entering into the mitotic phase. The therapeutic efficacy and toxicity profile of weekly paclitaxel administration have been showed since 90s. Lipidomics may be defined as the large-scale study of pathways and networks of cellular lipids that is involved in biological systems. In the present study our aim was to evaluate the possibility to identify a lipidomic signature of good and bad responsers to neoadjuvant chemotherapy.

PURPOSE: To analyze and identify the lipid fingerprint in tumor biopsy of advanced breast cancer patients who get a complete pathologic response (CPR) with weekly paclitaxel treatment and compare this with the group who get no response.

MATERIALAND METHODS: Seventy eight patients with clinical stage IIIA breast cancer were selected to receive the neoadjuvant treatment with weekly paclitaxel (for a total of 12 doses — 80mg/m2). Fifty eight patients completed the treatment purpose. Seven presented CPR (Group A) and 5 showed progressions (Group B). The lipids were extracted from biopsies and submitted to matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). MALDI-MS spectra were acquired in the positive ion and reflectron modes using Synapt Q-ToF mass spectrometers (Waters, Manchester, UK). The spectra were acquired in the m/z 700–1200 range. From each spectrum the most intense ions were considered as the starting point of searching m/z values which were clearly distinct from noise level in the spectra were included in the principal component analysis (PCA).

RESULTS: The PCA analysis of the mass spectra shows that groups can be resolved via their MALDI-MS lipid profiles, which suggest the patients who presented CPR can present distinct lipid fingerprint in the tumor biopsy compared to patients who showed progressions.

CONCLUSION: After genomic and proteomic innovations, it turns necessary to explore metabolic processes at the system level. Lipidomics is a developing strategy for functional genomics, since there is growing evidence that lipids are structural biomolecules, which have important function as signal transduction processes, second messenger molecules or their precursors. Is possible that lipidomic profile of tumor specimen could help us to select the patients with advanced breast cancer that might present complete pathologic response by weekly paclitaxel treatment. This study will be continued to confirm this results and carried the identification of the lipids based on earlier studies and MS/MS data using lipidmaps and chemspider databases.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-06.