bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor location does not influence the survival effects of radiotherapy in node-negative breast cancer.
Authors: Royce M , Bouchardy C , Rapiti E , Vlastos G , Cserni G , Vinh-Hung V , Lamote J , Storme G , Nguyen NP , Truong PT
Published: December 2010

Abstract #4134

Background  Medial (inner quadrants) tumor location has been shown to adversely influence survival in breast cancer. We investigated whether tumor location should alter the choice of local-regional treatments (surgery, with or without radiation therapy - RT), in women with node-negative breast cancer.  Materials and methods  Data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) 2006's database for 58,709 women aged 25-95 years, diagnosed between 1988-1997 with non-metastatic T1-2 node-negative breast cancer, who underwent breast conserving surgery (BCS) and axillary dissection. We used Cox proportional hazards to examine the effect of tumor location (medial versus other) on overall mortality after accounting for other prognostic factors (covariates listed in footnote table 1) and interactions identified by the Akaike Information Criteria.  Results  There were no notable differences in patients' characteristics according to tumor location. Among them, 25,232 had BCS, 33,477 had mastectomy. However the distribution according to the use of adjuvant RT showed marked heterogeneity. RT was used in 88% of BCS and in 3% of mastectomy patients. In the multivariate analysis that adjusted against the imbalances, medial location was associated with an increased mortality, hazard ratio (HR) 1.08 (95% confidence interval 1.04-1.13). Mastectomy had no significant impact on survival, HR=0.99 (0.92-1.07). RT was associated with a significant mortality reduction, HR=0.81 (0.75-0.88). There was no interaction between tumor location and surgery, or between tumor location and RT, while the interaction between surgery and RT was significant, HR=1.31 (1.14-1.51). The corresponding factorial summary showed no subgroup effect of tumor location: RT after BCS was associated with the same mortality reduction of 19% regardless of tumor location, and RT after mastectomy was associated with the same relative increase of 7% regardless of tumor location (Table 1).  Conclusion  We confirm the poorer prognosis associated with tumor medial location. However there was no subgroup effect. The survival outcomes of local-regional treatments were not affected by tumor location, arguing that tumor location is not a sufficient indication to modify local-regional treatments in node-negative patients. Local-regional treatment should be based on tumor characteristics and not tumor location.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4134.
Evaluating the cosmetic outcome of breast reconstruction: a comparison of patients' and healthcare professionals' views and their associations with patient satisfaction and quality of life.
Authors: Potter S , Thomson HJ , Greenwood RJ , Cawthorn SJ , Beresford M , Calder MI , Rayter Z , Winters ZE
Published: December 2010

Abstract #4135

Introduction: Objective cosmetic assessment, performed by surgeons, has traditionally been used to evaluate the success of breast reconstruction (BR). It is unclear however, how this assessment relates to the patient's perception of the cosmetic outcome their reconstruction or to other key patient-reported outcomes such as satisfaction or health-related quality of life (HRQL). Here for the first time, we compare patients and healthcare professionals (HCPs) assessments of the cosmetic outcome of their breast reconstruction and evaluate whose opinion, if any, is associated with health-related quality of life (HRQL) and patient satisfaction.  Methods: Women who had undergone immediate latissimus dorsi breast reconstruction between 6 and 60 months previously completed a study-specific cosmetic outcome questionnaire and 4 HRQL-instruments (EORTC-QLQ-C30+BR23, FACT-B, Body Image Scale (BIS) and HADS). Standardised 4-view photographic assessment was also performed for each woman and evaluated by a panel consisting of a breast surgeon, clinical oncologist, breast research nurse and female layperson. Weighted kappa statistics were used to investigate the agreement between patients' and panel members' evaluations of cosmetic outcome and overall patient satisfaction and Spearman's rank correlation was used to evaluate the association between these scores and HRQL domains. Full ethical approval was obtained for the study.  Results: 75 women completed questionnaires and attended for photographic assessment. Poor agreement was seen between patient and panel cosmesis scores, ranging from kappa = 0.19 (lay person/patient) to kappa = 0.27 (oncologist/patient). Significant agreement was seen between the patient's assessment of cosmetic outcome and their overall satisfaction with their reconstruction (kappa 0.52), but there was no agreement between patients' overall satisfaction and the panel's assessment of cosmesis (kappa 0.02-0.27). Good cosmetic outcome, regardless of rater, however was associated with better body image scores and improved HRQL as assessed by total FACT-B-scores.  Conclusions: Following breast reconstruction, cosmetic outcome appears to be associated with HRQL. Patients and HCPs, however, view cosmetic outcome very differently and ultimately only patients' cosmetic evaluation scores showed a good agreement with overall satisfaction, arguably the most important outcome of reconstructive surgery of this kind. The study suggests that traditional surgeon-led cosmetic assessments are of limited value in evaluating the true outcome of reconstruction and highlights that patient-reported outcomes should form an integral part of the comprehensive assessment of the success (or failure) of reconstructive surgery.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4135.
Early arm swelling predicts development of lymphoedema after axillary clearance.
Authors: Morais SA , Morris J , Heslop T , Newcombe RG , Townson J , Mansel R , Bundred NJ , Trialists on Behalf of the ALMANAC
Published: December 2010

Abstract #4137

Lymphoedema (≥10% increase in arm swelling) occurs in 30% of patients after axillary clearance but the factors predicting the development of early lymphoedema (within 18 months of surgery) are unknown. To determine factors predicting lymphoedema at 18 months we analysed the ALMANAC trial database.  Methods: All patients had baseline and prospective tape arm measurements, prior to undergoing axillary dissection and statistical analysis of 13 management variables affecting lymphoedema was performed.  Results: Out of 407, 91 (25%) underwent axillary sampling and the remainder had clearance surgery. Mean increase in arm volume was 4.02% and 5.14% at 3 and 6 months respectively. By 18 months, 148 (36%) women out of 407 had developed lymphoedema.  Arm volume increases of 5% or greater at 3 or 6 months predicted development of lymphoedema by 18 months (p≤0.01) and identified 56% of patients with lymphoedema at 18 months. Increase in age (p=0.039), extent of axillary surgery (p=0.045) and breast radiotherapy (p=0.022) were also significant predictors of lymphoedema at 18 months. In multivariate analysis only early arm swelling remained predictive of lymphoedema.    Conclusions: Early arm swelling after axillary clearance predicts early lymphoedema. Baseline arm measurement of patients undergoing axillary clearance should be routine preoperative care to identify women who need early intervention with arm compression sleeves.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4137.
Long-term follow-up results of endoscopy-assisted breast surgery (EBS) for early breast cancer.
Authors: Yom C , Min H , Park Y , Bae W
Published: December 2010

Abstract #4145

Introduction: Although endoscopy-assisted breast surgery(EBS) for early breast cancer had shown the excellent cosmetic outcomes, the application of ESSB is still controversial because of the scanty evidence of long-term safety and feasibility. This study is to evaluate the long-term outcome of endoscopy-assdisted breast surgery compared to conventional breast surgery for early breast cancer.  Patients and Methods: Between January 2002 through December 2006, 76 patients(Group E) who had diagnosed breast cancer underwent EBS at Sungkyunkwan University Kangbuk Samsung Hospital. 52 patients(Group O) not greater than stage 2A who had undergone conventional breast surgery during same period were enrolled in this study. The clinicopathologic characteristics, postoperative outcomes, hospital courses, and long-term outcomes including cancer recurrence and 5 year survival were retrospectively compared between two groups. The survivals of all the patients were confirmed with 58.4 month median follow up duration. Results: Tumor sizes were larger in Group O than in Group E(p=0.000). Harvested lymph nodes were more in Group O than in Group E(p=0.000). Postoperative recovery was significantly faster in the Group E; drain was removed earlier(p=0.001) and the postoperative hospital stay was shorter(p=0.001). The mean operation time was significantly longer in the Group E(p=0.000). There were no differences in the operation related morbidity and mortality between the two groups. In comparison of adjuvant therapy, Group O were received more chemotherapy than Group E(p=0.018), but there were no statistical differences of radiotherapy and hormonal therapy between two groups. Subjective cosmetic results were excellent in 63.6% and good in 18.2% more than 1 year after surgery. There was follow-up loss in 3 cases. Cancer-related death occurred in only 1 patient(0.7%) in Group O. The overall 5-year survival rate(5YSR) of the Group O and Group E were 98.2% and 100% , repectively. The disease-free 5YSR of Group O and Group E was 91.3% and 86.9%, repectively. There were no statistical differences on the overall and disease-free 5YSR between the two groups(p=0.446, p=0.205). Cancer recurrence occurred in 5 cases including 2 local recurrences, 2 distant metastases, and 1 second non-breast primary cancer in Group O and 6 cases including 2 local recurrences, 2 regional recurrences, 1 distant metastasis and 1 second non-breast primary cancer in Group E and there was no statistical significance between two groups(p=0.787).  Conclusions: Although the number and the qualification of the patients were so limited, our data suggest that endoscopy-assisted skin sparing breast surgery for early breast cancer is feasible and safe comparing to conventional breast surgery. We expect the results of the present study to be confirmed by prospective randomized analysis.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4145.
The use of an equine collagen fleece (Gentafleece®) in T1 breast cancer surgery: preliminary results.
Authors: Buonomo O , Piccirillo R , Caramanica A , Andrich R , Tirelli C , La Pinta M , Scardamaglia F
Published: December 2010

Abstract #4147

Introduction: A prospective multicentric randomized study is being conduced by Breast Cancer Surgical Group of Rome in order to evaluate the benefits of the use of equine collagen (Gentafleece®) on surgical and aesthetic outcome in T1 breast cancer patients.  Materials and Methods: One hundred and sixty T1 breast cancer patients have been randomized in two groups by four Roman Institutions in order to evaluate the potential clinical benefits of the use of equine collagen and gentamicine fleece (Gentafleece®). The parameters we studied and compared into the Gentafleece® and control group were: patients'satisfaction, seroma, hematoma, infections, fibrosis and aesthetic result. Both the groups underwent clinical and Ultrasound evaluations after One, Two, and Six months.  Results: Belonging to Gentafleece® group, seroma was detected in 7 (5,6%) pts, hematoma in 4 (3,2%) cases, fibrosis and surgical suture aesthetic distortions in 14 (11,2%) pts. On the other hand, in control group were found: 20 (16%) cases of hematoma; 32 (25,6%) cases of seroma; 22 (17,6%) cases were represented by parenchimal fibrosis associated to surgical suture distortions. One case (0,8%) of so defined “reactive megalomasty” occurred in a patient previously treated by neo adjuvant chemotherapy (Gentafleece® group). One case (0,8%) of dermatitis occurred in the same group. In many cases the complete healing of surgical suture was anticipated into first Group. Infection or suture dehiscences occurred in two cases (1,6%) treated by Gentafleece® beside 13 cases (10,4%) of the control group.  Discussion: This preliminary study seems to demonstrate that Gentafleece®, equine collagen and gentamicine fleece, is able to reduce the impact of seromas, ematomas, parenchimal fibrosis and surgical sutures and parenchimal aesthetic distortions in according to collagenic properties of cicatrization and hemostatic response. Furthermore Gentafleece® affords a significative antiinfective protection against surgical infection or suture dehiscence.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4147.
Feasibility study on radiofrequency ablation followed by partial mastectomy for stage I breast cancer patients.
Authors: Imoto S , Wada N , Sakemura N , Hasebe T
Published: December 2010

Abstract #4150

Backgrounds: Breast-conserving surgery (BCS) is a standard care for early breast cancer patients. However, local control is not sufficient for surgery alone and breast irradiation and hormonal treatment in hormone-sensitive tumor are recommended to reduce 10% or less of local failure rate. To evaluate the safety and reliability of thermal ablation therapy instead of BCS, we performed radiofrequency ablation (RFA) for clinical stage I breast cancer patients.  Patients and methods: The subject was T1N0 breast cancer patient with no extensive intraductal components. Under general anesthesia, sentinel node biopsy, and then RFA immediately followed by BCS was performed. Resected specimens were examined at 5 mm intervals by hematoxylin-eosin (HE) staining and several slices of tumor and non tumor lesions in each case were also evaluated by nicotinamide adenine dinucleotide (NADH) diaphorase staining.  Results: Thirty of the 34 eligible patients were enrolled (88%) about 2 years. Tumor diameters by ultrasound ranged from 9 mm to 24 mm. RFA-relating adverse events were observed in 2 cases of skin burn and 7 of muscle burn in major pectral muscle. There was one case of technical failure due to insufficient electrode replacement into the tumor. Twenty-eight cases (93%) revealed pathological degeneration changes of tumor specimens with HE staining. However, 2 cases had viable tumor cells of intraductal components beyond ablated breast tissues. In 24 of the 26 cases (92%) examined by NADH diphorase staining, tumor viability was diagnosed as negative. Finally, the complete ablation rate was 87% (26/30).  Conclusions: RFA proved to be reliable and feasible in clinical stage I breast cancer without extensive intraductal components. RFA will be an alternative to BCS as surgical treatment in such a case. Randomized clinical trials to compare RFA with BCS in breast cancer should be required.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4150.
Protein levels of NAD(P)H:quinone oxidoreductase 1 and p53 correlate in breast tumors.
Authors: Hubackova M , Vaclavikova R , Kodet R , Mrhalova M , Kubackova K , Gut I , Soucek P
Published: December 2010

Abstract #4157

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is integral flavoprotein responsible for detoxification and metabolism of quinoid compounds. NQO1 protects cells against accumulation of genotoxic quinoids, oxidative stress and stabilizes p53 from proteasomal degradation. The aim of this study was to follow the NQO1 role in breast carcinogenesis.  Methods: Levels of NQO1 transcript were monitored in frozen tumor samples by real-time PCR with absolute quantification. NQO1 protein levels were evaluated by immunohistochemistry in paraffin-embedded tumor samples. NQO1-Pro187Ser polymorphism was assessed in lymphocyte DNA by PCR with restriction fragment analysis.  Results: High interindividual variability in NQO1 expression among patients was observed. Wild-type genotype samples expressed NQO1 protein more often than heterozygotes (p=0.004; Fisher's exact test). We found strong correlation between NQO1 transcript and protein levels (p=0.004; T-test). Moreover, samples with negative NQO1 protein expression were often also negative for p53 expression (p=0.037; Fisher's exact test). No significant association of NQO1 levels and/or polymorphism with clinico-pathological characteristics of patients was found.  Conclusions: One of major findings of this study is the observed correlation of protein levels of NQO1 and p53 in breast tumors. Ability of NQO1 to modulate the degradation of p53 in the 20S proteasome was previously reported by use of cell lines and animal models [1]. Our results obtained by the use of real tumor samples further support this concept and suggest that NQO1 may play important role in carcinogenesis.  This study was supported by grants of Internal Grant Agency of Ministry of Health of the Czech Republic, no.: 9426-3, Grant Agency of the Czech Republic 305/07/P347 and the Grant Agency of Charles University, no.: 94507.1. Asher G, Lotem J, Kama R, Sachs L, Shaul Y: Proc Natl Acad Sci USA 98(3): 1188-1193, 2001.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4157.
The role of ABCB1 transporter gene in breast cancer resistance.
Authors: Vaclavikova R , Nordgard SH , Alnaes GA , Hubackova M , Hlavata I , Kodet R , Mrhalova M , Pecha V , Kristensen VN , Gut I , Soucek P
Published: December 2010

Abstract #4158

Background: Cellular multidrug resistance (MDR) to anticancer drugs remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters belong to a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. The aim of this study was to assess the role and clinical impact of ABCB1 and other ABC transporter-related genetic factors in development of MDR.  Material and Methods: Expression profile of ABC transporter genes (ABCB1, ABCC1/2, ABCG2) was evaluated in 90 breast cancer patients. Gene expression was quantified in samples from tumor and non-tumor breast tissues by real-time PCR. In addition, seven ABCB1 polymorphisms (SNPs) were analyzed using Nanogen electronic microarrays and compared with High Resolution Melting Analysis. Determination of associations between: 1/ expression of ABC transporters, 2/ genetic variability and 3/ haplotype pattern of ABCB1 on one side and clinico-pathological features including survival of patients on the other side was performed.  Results: ABC transporters were expressed in majority of cases. Striking inter-individual variability in their expression was found. ABCB1 was down-regulated in 79.5% of all tumors, while opposite was observed for ABCC1/2 expression. Similar expression profiles were found in patients treated by neoadjuvant and adjuvant chemotherapy. Patients with high ABCB1 expression treated with P-gp substrates anthracyclines or taxane containing regimens had significantly shorter disease-free survival than those treated by other regimens (P = 0.031). In genetic variation studies, high frequencies of variant alleles in ABCB1 exon12 (C1236T, qT=38.3), exon21 (G2677T/A, qT=40.0) and exon26 (C3435T, qT=54.0) were observed. Individuals with variant alleles in exons12 and 26 had significantly lower ABCB1 expression in their tumors than patients with normal genotype. These two SNPs also correlated with estrogen receptor status of patients (P=0.011 and P=0.051 respectively).  Conclusions: ABCB1 SNPs may affect function of protein by influencing the expression level and modify breast cancer prognosis. Especially, SNPs in exons 12 and 26 influenced ABCB1 expression and seem to be good candidates for cancer association studies. The observed association of ABCB1 SNPs with estrogen receptor status of patients warrants further research based on extended haplotype analysis. Moreover, high expression of ABCB1 in tumor tissue is considered to be an increased risk of failure of anthracycline or taxane-based chemotherapy. This work was supported by grants IGA 9426-3 and GACR 305/07/P347.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4158.
Breast cancer, dermatofibromas and arsenic.
Authors: Dantzig P
Published: December 2010

Abstract #4160

Background: Dermatofibromas are common benign tumors in women and breast cancer is the most common malignancy in women and an environmental etiology has been suspected in both conditions. The aim of this study is to determine if there is any relationship between the two conditions.  Materials and Methods: 5 patients with dermatofibromas and 10 control patients(2 groups) had blood arsenic levels and their skin biopsies measured for arsenic by inductively coupled mass spectometry. Fifty randomly selected patients with breast cancer and 50 control patients were examined for the presence of dermatofibromas.  Results: The patients with dermatofibromas had no detectable blood arsenic but the dermatofibromas were found to have an arsenic concentration of .171 micrograms/gram. One control group(5 patients) with no detectable blood arsenic had a skin concentration of .07 micrograms/gram and the other control group (5 patients) with an average blood concentration of 6 micrograms/liter had a concentration in their skin of .06 micrograms/gram. 43/50 patients with breast cancer had dermatofibromas and 32/50 had multiple dermatofibromas, compared with 10/50 control patients with dermatofibromas and only 1/50 with multiple dermatofibromas. In all breast cancer patients, the dermatofibromas preceded the breast cancer by many years though none of the patients could give an exact answer to that question.  Conclusions: Dermatofibromas may represent a reservoir for arsenic and may interfere with the rapid excretion of arsenic resulting in prolonged exposure. Arsenic may be important to the development of dermatofibromas as shown by the proliferation of endothelial cells, the main target of arsenic toxicity, and the increased melanin and hemosiderin, the classic causes of hyperpigmentation in chronic arsenic toxicity.Dermatofibromas represent a sign of chronic arsenic exposure, a powerful environmental carcinogen, 5-20 years prior to the clinical signs of breast cancer, when the changes in the cells would first be developing. This is the first time that any link to an environmental carcinogen has been shown in breast cancer and may represent an important venue to dramatically decrease the number of cases in the future. The dermatofibroma, especially multiple dermatofibromas, represent an important cutaneous sign of women at risk for breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4160.
Endoplasmic reticulum-associated calcium regulates taxol-induced apoptosis in breast cancer cells.
Authors: Pan Z , Gollahon L
Published: December 2010

Abstract #4163

Background: The body eliminates unhealthy cells through programmed cell-suicide called apoptosis. Calcium (Ca2+), one of the key regulators of cell survival, is also important in regulating apoptosis. Although the chemotherapeutic agent Taxol employs apoptosis to induce cell death in breast cancer treatment, the exact mechanism of how it induces apoptosis and the role of Ca2+ in this process remain unclear. The endoplasmic reticulum (ER), the main intracellular Ca2+ store, is newly-recognized as an important gateway in apoptosis, and possibly provides a target for Taxol.  Objective/Hypothesis: Putting these facts together, our hypothesis is that ER Ca2+ changes induced by Taxol determine breast cancer cell susceptibility to apoptosis and thus play a key role in ER-associated apoptosis. Therefore, this study investigated whether Ca2+ changes, especially associated with the ER, were generated and related to this apoptotic event.  Study Design and Methods: For this study, we used the MDA-MB-468 breast cancer cell line. The dynamic Ca2+ changes induced by Taxol were determined in living breast cancer cells by two methods: free cytosolic Ca2+ changes were measured using Fluo4-AM Ca2+ dye; and ER Ca2+ changes were measured by a novel Ca2+ cameleon, D1ER. After inducing and evaluating Taxol-induced apoptosis in this breast cancer cell line, the effects of different Ca2+ interfering agents on the apoptotic event were tested to determine whether Taxol-induced apoptosis is Ca2+ dependent.  Results: Taxol has a direct effect on Ca2+ homeostasis. Taxol induces a rapid ER Ca2+ release and results in a transient increase in cytosolic Ca2+ levels. A gradual ER Ca2+ depletion developed and contributed to the final sustained cytosolic Ca2+ increase. Interfering with these Ca2+ changes inhibited the Taxol-induced apoptosis, indicating that ER Ca2+ promotes Taxol-induced apoptosis.  Relevance: It is critical to understand the process through which the widely used anticancer agent Taxol induces apoptosis. This research addressed the question of whether intracellular Ca2+ changes play a critical or marginal role in mediating Taxol-induced apoptosis. Elucidating the role of calcium in this process will not only help to clarify the mechanism of Taxol, but also aid in more effective application of Taxol in breast cancer treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4163.
Breast cancer treatment delay in African American women in Washington, DC.
Authors: Landau J , Sagy N , Young H , Alexander L , LaVerda N , Levine P , Patierno S
Published: December 2010

Abstract #4164

Background: Delays in follow-up after a positive breast cancer screen are thought to contribute to racial/ethnic disparities in breast cancer outcomes. The goal of this study was to determine the relative impact of self-identified race and other relevant socio-demographic and logistic variables on time to diagnosis after an abnormal mammogram, and time to first treatment after a cancer diagnosis within the context of data collection for a large research study of the effectiveness of patient navigation.  Methods: Our sample includes 168 African-American and non-Hispanic white women with a documented invasive breast cancer diagnosis at an urban academic medical center during 2006 and 2007. The outcome variables were the number of days from abnormal mammogram to cancer diagnosis and from diagnosis to first treatment.  Results: The median number of days to breast cancer diagnosis following an abnormal mammogram was 20.5 days for African-Americans compared to 15 days for non-Hispanic white women. Median days to first treatment after diagnosis was 21 days for African-American women compared to 16 days for non-Hispanic white women. Neither difference was statistically significant. In addition, 76% of African-American women had private insurance versus 81% of non-Hispanic white women.  Conclusions: The identification of specific risk factors associated with a delay in diagnosis noted elsewhere in the literature and suggested in these preliminary findings could provide useful information regarding characteristics of women who are most likely to benefit from enhanced patient navigation efforts. Thus far, no statistically significant differences have been identified but the variety of factors that could contribute to the longer delay in disease management in African-American women compared to non-Hispanic white women, such as insurance status, provider location, household income, cultural issues, and other barriers to health care access, should be evaluated with a larger patient population.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4164.
The chemoresistant population of luminal subtype human breast cancer cells expresses a basal phenotype.
Authors: Kabos P , Dye WW , Elias A , Horwitz KB , Sartorius CA
Published: December 2010

Abstract #42

Background: We recently identified rare cells that express cytokeratin 5 (CK5+) and lack estrogen and progesterone receptors (ER– and PR–), in solid tumor xenografts derived from ER+PR+ T47D luminal A subtype human breast cancer cells (Horwitz et al, 2008 PNAS 105: 5774). These rare CK5+ cells have the capacity to re-form the majority of ER+PR+CK18+ cells in luminal tumor xenografts, and recapitulate the original tumor heterogeneity. CK5 is a marker of the poor prognosis basal-like subtype of human breast cancers. Additionally, CK5 is postulated to be a marker of stem/progenitor like cells in the human breast, and we have shown that CK5+ cells co-express the breast cancer stem cell marker CD44. We postulated that these rare basal-like CK5+ cells represent a potential chemoresistant subpopulation within luminal tumors. To test this, we used T47D and MCF7 cells, both of which have been classified by genetic profiling as luminal A (ER+PR+CK18+HER2–).  Methods: Cells were plated at subconfluent densities in serum-containing media and treated with either vehicle or cyclophosphamide (1mM), 5-fluorouracil (150μM) or docetaxel (11nM) for 72 hours; these doses were determined to yield a one to two-log kill. Residual chemoresistant cells were fixed: i) immediately following chemotherapy, or ii) after colony repopulation for 7 days. The chemoresistant subpopulation was characterized by immunocytochemistry for markers of basal/stem and luminal phenotypes, including CK5, ER, PR, CK18, and CD44.  Results: At baseline, as well as in controls, both cell lines were ER+PR+CK18+ and ER–PR–CK5+ cells were rare or undetectable. In response to treatment with each of the three drugs, the surviving population was enriched in ER–CK5+ cells. PR expression was variable (+/–) in CK5+ cells. These chemoresistant cells were able to repopulate colonies that expressed ER+PR+CK18+ and resembled the original cells by having a predominant luminal phenotype, with only rare/undetectable receptor negative, CK5+ basal-like cells.  Conclusion: We conclude that luminal subtype human breast cancer cells contain a rare basal/stem-like chemoresistant subpopulation that is capable of repopulating a luminal tumor after therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 42.
Intensive breast cancer screening programs including MRI influence prognosis and treatment of breast cancer among BRCA 1/2 gene mutation carriers.
Authors: Chereau E , Uzan C , Chevalier J , Bressac-de Paillerets B , Caron O , Mathieu M , Koskas M , Bourgier C , André F , Dromain C , Balleyguier C , Delaloge S
Published: December 2010

Abstract #5004

Background: Several studies have highlighted the potential benefit of early breast cancer (BC) diagnosis through breast MRI for high risk patients (pts). However, MRI is an expensive test with a low positive predictive value and has not been proven to reduce mortality rates in women carrying BRCA1/2 deleterious gene mutations (mut).  At Institut Gustave Roussy, we started intensive BC screening programs for BRCA1/2 carriers (annual MRI + mammogram + bi-annual US) in 2001. The aim of this study was to compare the characteristics and prognostic features of BC in BRCA1/2 pts diagnosed inside or outside screening programs.  Patients and Methods: All female BRCA1/2 mut carriers who have been treated for a new BC in our institution between 2001 and 2008, were entered into this study. All BRCA1/2 mut testing have been performed under the French guidelines and recommendations.  We compared the clinico-pathological data, treatments and prognostic features between group 1 (pts diagnosed while on an intensive dedicated screening program) and group 2 (pts diagnosed outside these programs). Pts characteristics were compared using student T-test, and survival curves using Log-Rank tests.  Results: 122 pts met the inclusion criteria: 20 in group 1, 102 in group 2. > 95% of pts in group 2 were not aware of their BRCA1/2 mut at time of diagnosis. In group 1, 17 cancers were diagnosed primarily through MRI (85%), while 3 were self-detected interval BC. Pts in group 1 had tumors with significantly better prognostic factors and received less CT.  3-year DFS significantly differed between groups 1 (100%) and 2 (74% (IC: 64-81 (p=0.04). 3-years MFS was 100 and 80% (p= 0.08), 3-years OS was 100 and 94% (p=0.26) in groups 1 and 2.    Conclusion: These early data strongly suggest an important benefit in terms of disease-free survival and treatment sparing for i. the knowledge of a BRCA1/2 mut; ii. inclusion into intensive BC screening programs including MRI.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5004.
Method of detection is a prognostic factor for outcome among women diagnosed with early stage breast cancer.
Authors: Brewster AM , Thompson PA , Cao Y , Murray JL , Stewart MM , Berry DA , Bondy ML
Published: December 2010

Abstract #5005

Background: The reduction in breast cancer mortality over the past several decades has been partially attributed to the impact of screening mammograms. Breast cancers detected by screening mammograms tend to be at an earlier stage than those detected as a result of symptoms. The magnitude of the impact of method of detection on breast cancer survival beyond this phenomenon, known as stage shift, is not well defined. We therefore evaluated the independent prognostic effect of method of detection among women diagnosed in early stages of disease (stage I and II breast cancers). Methods: Medical records from 2,143 women aged 40 or older with stage I and II breast cancers, treated at the M.D. Anderson Cancer Center between 1985 and 2000 were used to derive information on method of breast cancer detection, clinical and histological tumor characteristics. Cox proportional hazards models were used to estimate the hazard ratios (HR) of breast cancer recurrence and breast cancer-specific death adjusted for age at diagnosis, year of diagnosis, nuclear grade, hormone receptor status, systemic treatment and stage at diagnosis. All statistical tests were two-sided. Results: Patients ages 40-49, 50-69 and ≥70 with symptom compared to screen-detected breast cancers were statistically significantly more likely to be diagnosed with stage II versus stage I disease and were more likely to have higher nuclear grade III versus grade I tumors. Symptom-detected breast cancers were associated with an increased risk of breast cancer recurrence (HR 1.9, 95% confidence interval (CI) 1.4-2.6) and breast cancer-specific death (HR 2.0, 95% CI 1.4-3.0) than screen-detected breast cancers after adjusting for age at diagnosis, year of diagnosis, tumor size, lymph node involvement, tumor characteristics and systemic treatment. Discussion: Our data from a large cohort of breast cancer patients with long-term follow-up indicate that even among patients with early stage disease; those with symptom-detected breast cancers have a worse prognosis. Consideration should be given to including method of detection as a prognostic factor when making treatment decisions for patients with stage I and II breast cancers.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5005.
Is the incidence of breast cancer among Asian women living in the UK, higher at a younger age than that of the Caucasian women?.
Authors: Ullah MZ , Pericleous M , Jamal-Hanjani M , Pereira B , Snooks SJ , Keshtgar M , Davidson T
Published: December 2010

Abstract #5011

Introduction: The South Asian population comprises 3% of total UK population. An observational study showed that the Asian women living in the London boroughs of Redbridge and Camden present at a younger age with breast cancer than their Caucasian counterpart. This raises the question as to whether or not an earlier intervention with breast screening would be beneficial for this group.  Methods: To verify our study, we audited two centres in these London boroughs. The patients with breast cancer from areas with a higher concentration of women of South Asian ethnic origin have been audited from January 2000 to December 2007 (Total 9 years). The borough of Redbridge has an Asian population of 25% from a total of 240,000 residents and Camden has an Asian population of 10.4% from a total of 198,000 residents. Data was collected from the breast units and from patient databases of King George Hospital and Royal Free hospital, London, UK.  Results: A total of 1314(513+801) patients presented with breast cancer from January 2000 to December 2004 at King George Hospital and from January 2002 to December 2007 at Royal Free Hospital. 147(11.18%) of these patients were of South Asian origin (Indian, Pakistani, Bangladeshi, Sri Lankan) and 1149 (87.44%) were Caucasian. The age at which breast cancer was presented for the Caucasian population ranges from 25 to 99 years with a mean of 65.16 in contrast to the age for the Asian population which ranges from 31 to 78 years with a mean of 54.04.  Conclusions: The finding of a lower mean age of incidence of breast cancer amongst South Asian women in Redbridge and Camden raises the increased possibility of breast cancer occurring among younger women of the South Asian population in general, compared to Caucasian women living in the United Kingdom. The evidence of a generally younger age of presentation of breast cancer in Asian women living in the UK suggests that more awareness of this condition is needed amongst this group. Therefore, an earlier breast screening programme will possibly increase the chances of early detection of breast cancer among this group of patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5011.
The value of mammography vs. physical examination in detecting a recurrent breast cancer in women with a previous diagnosis of breast cancer.
Authors: Elmadhun NY , Finlayson CA
Published: December 2010

Abstract #5014

Background: The value of mammography in detecting early breast cancer has been firmly established, however the benefit of mammography in detecting recurrent breast cancer has not been clearly elucidated. The purpose of this study is to determine the value of mammography versus physical examination in detecting a recurrent breast cancer in women with a previous diagnosis of breast cancer.  Methods: This is an IRB approved retrospective chart review. Fifty-eight patients were identified from our institution's Breast Center tumor registry who were diagnosed with stage I-II breast cancer from 1973-2006 and who subsequently developed a locoregional recurrence. The method of detection of the initial breast cancer was recorded and compared to the method of detection of the recurrent breast cancer.  Results: The mean age at the original diagnosis was 47 years (range 29-89 years). The mean time to recurrent breast cancer or second primary was 38 months (range 6-173 months). Seventeen patients (29%) were initially diagnosed with breast cancer by screening mammography. Of those 17, 3 (18%) were diagnosed with a recurrent breast cancer by mammography, and the remaining 14 by physical exam. Among the 14 patients that presented initially with a palpable breast mass and positive mammogram, 3 (21%) had recurrent breast cancer detected by mammography. Thirty-four patients (59%) initially presented with a palpable mass. Nineteen of these patients had mammograms, 5 did not have mammography, and 8 were unknown whether imaging was done. Of those 19 that had mammography, 14 were positive and 5 were negative. The 5 patients with palpable masses and negative mammograms all had mastectomies initially and their locoregional recurrence was detected by physical exam. Forty-nine patients (84%) had a clinical finding leading to the diagnosis of recurrent breast cancer and seven (12%) had recurrence identified by mammography. Two patients had unknown method of detection of recurrence. The clinical recurrences were identified in the axilla (53.4%), chest wall (12%), supraclavicular fossa (8.6%), breast (3.4%), and skin (3.4%).  Conclusions: One-third of patients with a recurrent breast cancer had their initial cancer identified by mammography but only 12% had their recurrence identified by mammography. Fifty-nine percent of patients were initially diagnosed by physical examination and 84% of recurrence was diagnosed with physical examination. Patients whose initial cancer was visible on mammogram are likely to have a recurrence also visible on mammogram. Though mammography is useful in detecting the first early stage breast cancer, most patients present with a clinical finding when they present with the recurrent breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5014.
Validation of OncoVue®, a new individualized breast cancer risk estimator in the Marin County, California adolescent risk study.
Authors: Dalessandri KM , Miike R , Wrensch MR , Wiencke JK , Benz CC , Pugh TW , Manjeshwar S , Jupe ER
Published: December 2010

Abstract #502

Background: Improved models for estimating individual breast cancer risk are urgently needed for guiding clinical decisions. The OncoVue model was developed by analysis of a large case-control study genotyped for 117 common, functional single nucleotide polymorphisms (SNPs) in candidate genes likely to influence breast carcinogenesis. Multivariate logistic regression analyses were used to develop a model employing 22 SNPs in 19 genes together with the Gail Model risk factors. In the original studies of the model building set and two independent validation sets, OncoVue exhibited improved individualized risk estimation, compared to the Gail Model alone, by correctly placing more cases and fewer controls at elevated risk. Here, we sought to examine the performance of OncoVue in women from the Marin County, California breast cancer adolescent risk factor study.  Materials and Methods: Buccal cell DNA was isolated from 177 controls and 169 age-matched women diagnosed with breast cancer between 1997 and 1999. All samples were anonymously coded to remove case-control status and provided to InterGenetics along with all other relevant personal history information. DNAs were genotyped for the 22 SNP variants in OncoVue and combined with personal factors to calculate the risk scores for the individual participants. OncoVue scores were then returned to the Marin County study investigators who conducted the analyses using case-control status.  Results: Positive likelihood ratios (PLR) were calculated as the proportion of patients with breast cancer with an elevated risk estimate (12%) divided by the proportion of disease-free individuals with an elevated risk estimate. For OncoVue the PLR was 2.2, whereas for the Gail Model the PLR was 0.9, demonstrating a 2.4-fold statistically significant (p=0.036) improvement. In additional comparisons using normalized control scores, OncoVue exhibited a 51% improvement compared to the Gail Model in assigning elevated risk to cases.  Conclusion: In this blinded validation study OncoVue exhibited significantly improved performance, compared to the Gail model alone, in estimating individual risk among Marin County, California women. The improved performance of OncoVue was similar to that observed in two previous independent validation sets, thus, supporting the clinical utility of OncoVue for more accurate individualized breast cancer risk estimation.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 502.
Monitoring cytokeratin19 (KRT19) levels as response of circulating tumor cells (CTC) to neoadjuvant chemotherapy (NAC) in breast cancer (BC).
Authors: Guerrero-Zotano AL , Garcia-Casado M , Fernandez-Serra A , Lopez-Guerrero J , Gavila J , Climent M , Ruiz A , Guillem V
Published: December 2010

Abstract #5022

Background: KRT19 mRNA+ cells before the initiation of adjuvant chemotherapy has been shown as an independent prognostic factor for disease recurrence in patients with early BC. Its usefulness for monitoring response to NAC it is not clear. We have studied changes in KRT19 levels during NAC and correlated it with response. Material and Methods: We analyzed a prospective series of 70 BC patients treated with NAQ. Stage II (45%), Stage III (55%), HR negative (43%), HER-2 positive (42%). Treatment was based on sequential anthracyclines and taxanes. Trastuzumab was given concomitant in HER2 disease. KRT19 level expression was measured from lymphocytes of peripheral blood using a quantitative RT-PCR. The analysis was performed at diagnosis (baseline), before taxane administration, at the end of NAC, and after surgery. On the other hand, 27 healthy donors and 18 metastasic BC patients were also analyzed in order to determine a cut-off value for CTC positivity according to receiver operating characteristics [ROC] analysis. Association between variables was performed by Pearson's Chi-squared and Fisher's tests. Results: We observed a differential rate in KRT19 expression, between the control and the metastasic series being higher in the last group (U-Mann-Withney test, p=0.010). According to the selected cut-off value (AUC 0.272; p=0.010), we detected CTC in 46/70 (65.7%) patients at baseline, 22/40 (55%) prior to taxane administration, 36/50 (72%) at the end of NAC and 13/17 (76.5%) after surgery.Forty out of 57 patients (70.2%) responded to NAC(15 CR and 25 PR). Decreased in CTCs levels during treatment wasn't associated with response, on the contrary, residual CTCs were detected after surgery in all those cases that responded (p=0.005). The presence of CTCs after completion of chemotherapy, previous to surgery, was inversely related to tumor stage (p=0.012). Negative tumors for HER2 and tumors with high levels of ER expression maintain the CTC levels detected at diagnosis (p=0.044 and p=0.057 respectively). DISCUSSION: We weren't able to find a correlation between response and decrease in CTCs levels. The presence of residual CTCs in responding cases could suggest a release of tumor cells into blood by NAQ and surgery The prognostic factor of residual CTCs needs to be addressed with longer follow up, and taking into account the effect of others therapies. This study is financed by the grant GVA07/130.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5022.