bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-11-13: Impact of Young Age on the Presentation, Management and Outcome of Breast Cancer in a Multi-Ethnic Asian Setting: Results from the Singapore-Malaysia Hospital-Based Breast Cancer Registry
Authors: Bhoo Pathy N , Yip C-H , Taib NA , Saxena N , Iau P , Bulgiba AM , Lee S-C , Hartman M , Verkooijen HM.
Published: April 2011

Background: The proportion of very young women with breast cancer is high in Asia, ranging between 10% and 25%. Material and methods: Within the multi-institutional Singapore-Malaysia hospital-based breast cancer registry, we compared tumor characteristics, treatment and survival of very young (<35 years; n=210) and older (35-55 years; n=2,152) breast cancer patients diagnosed between 1990 and 2007. Overall survival (OS)was estimated by Kaplan-Meier analysis. Cox regression analysis was used to compute hazard ratios (HR) after splitting follow-up time along the age-axis and calendar-time axis.

Results: Compared to older breast cancer patients, young patients presented with larger tumor (median diameter 25mm vs 30mm respectively: P<0.001), and less estrogen receptor positive (54% vs 46% respectively: P<0.01), and progesterone receptor positive tumors (57% vs 47%: P<0.01). Young women were more likely to receive chemotherapy (70% vs 61%: P<0.01), and less likely to be given hormone therapy (36% vs 57%: P<0.001).

Among those with stage 0 to stage II disease, 5-year OS was 71.3% (95%CI: 61.7%-80.9%) in young patients and 85.6% (95%CI: 83.2%- 88.0%) in older women. After adjustment for stage, tumor profile and treatment, young patients had approximately 50% higher risk of death than their older counterparts (HR:1.46; 95% CI: 1.23-1.73). Ethnicity, tumor size, pathological lymph node staging, loco-regional therapy, and chemotherapy, were significant independent predictors of overall survival among young patients with breast cancer.

Conclusion: Asian women diagnosed at a very young age, present with less favorable tumor characteristics and stage distribution. They have a 50% higher risk of death following their disease, which is independent of their stage at diagnosis, tumor characteristics and treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-13.
Abstract P3-11-14: Comparison of Breast Cancer Management at the Extremes of Age — A Single Centre Study
Authors: Dordea M , Jones R , Pujol Nicolas A , Sar S , Batson S , Fetherston A , Truran P , Solomon J , Iwuchukwu O.
Published: April 2011

Background: Literature describes age-dependent variations in breast cancer treatment, showing that older women are less likely to receive standard treatment than younger women. Statistically the elderly population is at highest risk of suffering from breast cancer. There is a renewed interest in discussing the issues around the management of breast cancer in the elderly age group, including a feeling of leniency or lack of aggressiveness in the overall management of such patients.

Methods: We undertook a retrospective analysis of 386 consecutive presentations of symptomatic breast cancer from 1998 to 2005. Patient demographics, tumour, treatment and outcome data were recorded. A cut off of <40 and >75 years of age was set to define our groups. Results: 69 cases of breast cancer in the ‘young’ age group and 255 cases of breast cancer in the ‘old’ age group were recorded. The younger patients had significantly more high-grade (BM Grade 3) tumours than their older counterparts (50.7 vs 26.6%, P<0.001) and a higher proportion of invasive ductal carcinomas (86.8 vs 73.1%, p=0.006). There were no significant differences in tumour size and node positivity between the two groups.

Discussion: Our results show that for similar tumour sizes and nodal status the elderly age group receives less surgical and adjuvant therapy. Despite under management of the ‘old group’ our ‘young’ group suffers from higher and earlier recurrence. The overall disease related mortality is similar in both groups, however significantly worse if the ‘young’ group is compared with the ‘old’ group receiving surgical intervention. We suggest that young breast cancer patients have a worse overall prognosis when compared to surgically fit elderly counterparts and that perceived gaps in management could be explained by lack of physiological reserve in the elderly (sister paper). Use of geriatric assessment tools in a multidisciplinary setting may help in targeting the surgically fit population and avoid under treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-14.
Abstract P3-12-04: RAD51 135G>C Does Not Modify Breast Cancer Risk in Non-BRCA1/2 Mutation Carriers: Evidence from a Meta-Analysis of 12 Studies
Authors: Yu K-D , Shao Z-M.
Published: April 2011

A single-nucleotide polymorphisms (SNP) in the 5'-untranslated region (UTR) of RAD51, 135G>C (rs1801320), was reported to be associated with an increased risk of breast cancer among BRCA2 as well as BRCA1 carriers. A few studies have also investigated the genetic contribution of RAD51 135G>C to the risk of sporadic breast cancers or breast cancer in non-BRCA1/2 carriers, though the results are yet controversial andinconclusive. We in this study performed a more precise estimation of the relationship between 135G>C and breast cancer among non-BRCA1/2 mutation carriers by meta-analyzing the currently available evidence from literature. A total of 12 studies involving 7,065 cases and 6,981 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. When all the studies were pooled into the meta-analysis, there was no evidence for a significant association between 135G>C and breast cancer risk in non-BRCA1/2 mutation carriers (for CC vs. GG: OR = 0.995, 95% CI: 0.741-1.336; for GC vs. GG: OR = 0.959, 95% CI: 0.869-1.057; for dominant model: OR = 0.988, 95% CI: 0.902-1.082; and for recessive model: OR = 1.037, 95% CI: 0.782-1.376).

We also performed subgroup analysis by ethnicity (Caucasian) as well as did analysis using the studies fulfilling Hardy-Weinberg equilibrium, and the results did not change. In summary, the present meta-analysis suggests that the RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-04.
Abstract P3-12-07: Polymorphisms in the UDP-Glucuronosyltransferase 2B Gene Family and Risk of Breast Cancer in Women of African Descent
Authors: Sun C , Huo D , Nemesure B , Hennis A , Witonsky D , Niu Q , Di Rienzo A , Olopade OI.
Published: April 2011

Background: The UDP-glucuronosyltransferase 2B (UGT2B) enzymes catalyze glucuronidation, which is an important clearance pathway of steroid hormones, and medications, and potential carcinogens. As steroid hormones play a central role in breast cancer development, genetic polymorphisms in the UGT2B gene family may affect breast cancer susceptibility.

Methods: We evaluate two missense mutations in UGT2B15 (rs1902023, D85Y and rs4148269, K523T), one missense mutation in UGT2B7 (rs7439366, H268Y), and one single nucleotide polymorphism (SNP) 497 bp upstream to UGT2B4 (rs13129471) using pooled case-control studies of breast cancer, which included 1,287 cases and 851 controls. Cases and controls were enrolled in Nigeria, Barbados, and the US, and all are women of African ancestry.

Results: All four SNPs followed Hardy-Weinberg equilibrium in each ethnicity group. We found the rs13129471 SNP was significantly associated with breast cancer risk after adjusting for ethnicity (P=0.003). Compared with homozygous genotype for the A-rs13129471 allele, the odds ratio for heterozygous genotype and homozygous genotype for the G-rs13129471 allele was 1.02 (95% CI: 0.81-1.28) and 1.50 (1.15-1.95), respectively. The association was stronger in Nigerian women (P=4x10- 5) and the corresponding odds ratio was 1.13 (95% CI: 0.85-1.49) and 2.39 (1.61-3.55). No significant association was found for the other three non-synonymous SNPs.

Conclusion: Our results suggest that polymorphism in the UGT2B4 gene may be associated with breast cancer risk in women of African ancestry and the association may follow a recessive model. The finding needs to be confirmed in other populations.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-07.
Abstract P3-12-11: Combining Genotype at Low Penetrance Breast Cancer Loci with Family History Risk Leads to Significant Risk Reclassification
Authors: Martin AJ , White S , Onen A , Gale J , Dunlop J , Baker L , Thompson AM , Pharoah PDP , Berg JN.
Published: April 2011

Background: A significant proportion of women are at increased genetic risk of breast cancer. Mutations in high penetrance genes such as BRCA1 and BRCA2 are only responsible in the minority of cases, with low penetrance polymorphisms in other genes expected to account for the majority of the remaining genetic risk. An increasing number of such low penetrance polymorphisms are being identified, but each polymorphism only contributes a small amount to overall risk. Currently, in clinical practice, women who are at increased risk of breast cancer are identified by their family history, and the role of genetic testing for multifactorial risk remains uncertain. We have taken the population frequency and genotype relative risk information for the 18 most established low penetrance breast cancer risk loci and explored the effect of combining information from these loci, with risk derived from family history. Results: Genotyping at these 18 loci could provide significant risk information for an individual. The top 1% of women in the genotype risk distribution would have a risk of breast cancer of 2.11 times the general population. At this level of risk, they would qualify for breast cancer screening from age 40 according to evidence based guidelines issued by the UK National Institute of Clinical Excellence (NICE). In addition, the top 5% of the population are at 1.67 times risk of breast cancer and would have the same risk at age 40 as a 50 year old at population risk who would qualify for breast screening according to UK and US National Screening Guidelines. To investigate whether low penetrance genotype has greater potential if combined with other risk factors, we used a simple multiplicative model to combine family history risk of cancer derived using BOADICEA with genotype information. Our data suggest that genotype would result in a significant reclassification of individual risk. For example, 10% of women who only had a sister affected with breast cancer at 55 would qualify for additional screening under NICE criteria if genotype were taken into account. Extending this approach with 160 complex family histories from the Tayside family history breast clinic, we have shown that genotyping could result in reclassification and change of management for 19.1% of women being assessed in this clinic, with 12.4% of women moving into a higher risk category, and 6.7% of women moving into a lower category. Discussion: These data suggest that genotyping for low penetrance breast cancer risk loci is clinically relevant, and that it will be more powerful if it can be combined with other established risk factors.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-11.
Abstract P3-12-12: HER2 Evaluation in Relation to Breast Cancer Treatment Decisions in a Managed Care Plan
Authors: Weinmann S , Goddard KAB , Richert-Boe KE , Chen C , Bulkley JE , Wax C.
Published: April 2011

Background: In 18-20% of breast cancer tumors, the human epidermal growth factor receptor 2 (HER2) gene is abnormally amplified with increased expression of the associated protein. HER2 amplification is associated with rapid tumor proliferation, shorter disease-free survival, and poorer overall survival. Because women with HER2 amplification are more likely to benefit from treatment with the drug trastuzumab, testing for HER2 is recommended to guide therapy. However, little is known about HER2 testing practices and associated treatment in real-world settings. This study examined uptake, use, and appropriateness of HER2 testing, and the relationship between HER2 test results and treatment decisions in a large integrated health system.

Methods: We identified 3,634 patients with primary breast cancer diagnosed from 1998-2007 who were members of the Kaiser Permanente Northwest health plan. We collected data on patient and tumor characteristics, HER2 testing status, test results, and trastuzumab treatment from tumor registry and pharmacy datasets. We defined women as evaluated for HER2 if they received HER2 testing by immunohistochemistry (IHC) and/or fluorescent in-situ hybridization (FISH). We manually abstracted medical charts for a subset of patients to verify findings and investigate anomalies. We compared testing and treatment results to professional guidelines. Results: From 1998-2000, the percentage of patients with invasive breast cancer who underwent HER2 evaluation increased from 12% to 94%; from 2000-2007, 94% (2304/2461) received HER2 testing over all years combined. In most cases, an equivocal or positive IHC test was followed by FISH. Only 2.4% of women with ductal carcinoma in situ (13/538), for whom HER2 testing is not recommended, were tested, and the proportion remained consistently low over the entire study period. Trastuzumab use increased five-fold after 2004, when guidelines expanded to include recommending adjuvant treatment for early-stage breast cancer in addition to metastatic treatment. Ninety-five percent of women receiving trastuzumab had a positive HER2 result, while the remainder had equivocal HER2 results or received treatment outside thedelivery system. After 2004, 55% of women with invasive breast cancer and overexpression of HER2 received trastuzumab treatment; this ranged from 44% of women with localized breast cancer to 80% of women with distant metastatic disease. We estimate that, after correcting for errors in the datasets, professional guidelines were followed for over 97% of patients diagnosed since 2000.

Conclusions: Kaiser Permanente Northwest is systematically performing HER2 evaluation on patients with invasive breast cancer, and the information is used to make appropriate treatment decisions. This information should be gathered in other health care settings for comparison.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-12.
Abstract P3-13-04: The Role of PSPHL in Breast Cancer in African American Women
Authors: Field LA , Rummel S , Shriver CD , Ellsworth RE.
Published: April 2011

Background: Younger age at diagnosis and poorer prognosis in African American women (AAW) with breast cancer have led to a number of studies evaluating gene expression differences in tumors from AAW compared to those from Caucasian women (CW). Studies have found that PSPHL expression is significantly higher not only in breast but also in prostate and endometrial tumors from African Americans compared to Caucasians. SNP rs6700 in the 3’ UTR of PSPHL has been found to correlate with expression. Here, we investigated how rs6700 affects PSPHL expression levels in AAW and CW with and without breast cancer.

Methods: Genomic DNA was isolated from 74 women with (35 AAW and 39 CW) and 37 women without breast cancer (23 AAW and 14 CW). rs6700

was genotyped using TaqMan SNP Genotyping assay C__314922_10.

PSPHL expression levels in breast tissue were measured in these same women using TaqMan Gene Expression assay Hs00863464_m1 using RNA isolated from laser microdissected breast tumor cells or normal breast tissue from women with or without breast cancer, respectively.

Results: PSPHL expression in breast tumors from AAW was significantly higher than in CW (P = 6 x 10-6). The median fold change in expression in AAW was 42.2; while only 2 (6%) AAW had no detectable expression of PSPHL, 21/39 (54%) CW did not express PSPHL. The minor allele frequency (T) in AAW with breast cancer was 0.41 compared to 0.06 in CW with breast cancer. In both AAW and CW, median levels of PSPHL expression were lowest (15.45 in AAW, 0 in CW) in women with the C/Cgenotype. In addition, all patients whose tumors had no detectable PSPHL expression had the C/C genotype. In women without breast cancer, the C/C genotype was also correlated with lower PSPHL expression and was more frequent among CW compared to AAW (79% and 39%, respectively).

Conclusions: PSPHL is more highly expressed in both diseased and normal breast tissue from AAW compared to CW and expression of PSPHL correlated with rs6700 genotypes. Although the function of PSPHL is unknown, it may function in cellular proliferation. Higher expression in AAW may, therefore, promote the development of tumors in AAW. It must be noted, however, that the frequency of the C allele is significantly lower in the African American population as a whole (53% vs. 92%); therefore, differences described here may reflect population differences rather than any specific contribution to breast cancer etiology. However, due to the higher expression of PSPHL in African Americans with other hormone-dependent cancers, its role in tumorigenesis requires further study.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-04.
Abstract P3-13-05: Estrogen Receptor-Positive Breast Cancer in Japanese Women: Trends in Incidence, Characteristics and Prognosis
Authors: Yamashita H , Iwase H , Toyama T , Takahashi S , Sugiura H , Yoshimoto N , Endo Y , Kobayashi S.
Published: April 2011

Background: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. Patients and Methods: We examined the characteristics of patients and tumors treated in three time periods between 1982 and 2010. Estrogen receptor (ER), progesterone receptor (PgR), and HER2 status were assessed by immunohistochemistry. Correlation of hormone receptor levels with clinicopathological factors and prognosis was analyzed in ER-positive, HER2-negative breast cancer in two age groups (≥50 years vs. >50 years).

Results: A total of 1903 women with breast cancer, who were treated at Nagoya City University Hospital, were included in this study. The frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982-1991: 52.5%, 1992-2001: 72.6%, 2002-2010: 87.1%, P < 0.0001). The frequency of ER-positive tumors was also significantly increased in women over 50 years of age (1982-1991: 69.4%, 1992-2001: 73.3%, 2002-2010: 78.6%, P = 0.029). In ER-positive, HER2-negative breast cancer, tumor grade was negatively correlated with expression levels of ER (P = 0.0029) and PgR (P < 0.0001). Interestingly, PgR levels were significantly higher in women aged 50 years or younger than in women over 50 years old (P < 0.0001). In both age groups, the prognosis for patients with ER-positive, HER2- negative breast cancer significantly improved over time, due to advances in adjuvant therapies. ER and PgR expression levels were not associated with disease-free survival. Lymph node status and tumor size were strong prognostic factors regardless of the biological characteristics of the tumors in ER-positive, HER2-negative breast cancer in both age groups. Conclusions: It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention. Furthermore, new approach should be considered to improve survival for node-positive, ER-positive breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-05.
Abstract P3-14-08: Responses to Subsequent Anti-HER2 Therapy after Treatment with Trastuzumab-DM1 in Women with HER2-Positive Metastatic Breast Cancer
Authors: Olson EM , Lin NU , DiPiro PJ , Najita J , Krop IE , Winer EP , Burstein HJ.
Published: April 2011

Background: Women with HER2-positive metastatic breast cancer (MBC) can have clinical responses to multiple lines of anti-HER2 therapy. However, it is unknown whether these patients will derive further clinical benefit following treatment with the novel antibody-drug conjugate trastuzumab-MCC-DM1 (T-DM1), which has significant activity in trastuzumab-refractory breast cancer.

Methods: We retrospectively identified patients treated with T-DM1 monotherapy on clinical trials for HER2-positive MBC at Dana-Farber Cancer Institute and characterized clinical outcomes during subsequent lines of anti-HER2 therapy. Response was determined by an independent and blinded radiology review using modified RECIST 1.1 criteria without confirmatory scans; patients without radiologic assessment were considered non-responders. Duration of therapy was defined from initiation of therapy until treatment discontinuation, and for patients continuing on therapy, times were censored at date of last visit; analysis was performed using Kaplan-Meier estimates.

Results: We identified 23 patients treated on protocol-based therapy with single-agent TDM-1 and report on the 20 patients who had discontinued protocol, and hence, T-DM1 therapy. All patients received trastuzumab in the metastatic setting prior to initiation of T-DM1, with a median number of 6 (range 1-14) prior regimens. Most (75%) were taken off study secondary to progressive disease and the remainder discontinued therapy for toxicity. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after concluding T-DM1; reasons for not receiving additional treatment after T-DM1 include death (3) and interruption of therapy due to physician or patient request (2). The majority (12 of 15; 80%) of patients treated beyond T-DM1 received a regimen containing either trastuzumab and/or lapatinib at some point during their course. Partial response to either first-or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib (Figure 1). Three patients did not have radiographic assessments; however, all 3 demonstrated clinically stable disease (as determined by review of clinical data) to first treatment after T-DM1. Median duration of therapy to first-subsequent regimen after T-DM1 was 5.5 months. Of the 9 patients that received a second-subsequent regimen, the median duration of therapy to the second-subsequent treatment was 6.4 months.

Conclusions: In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab and/or lapatinib-based regimens.

Maximum Decrease in Target Lesion Diameter

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-08.
Abstract P3-14-11: Trastuzumab Cardiac Toxicity and HER2 Polymorphism: A Case-Control Study
Authors: Mailliez A , Révillion F , Ploquin A , Servent V , Bonneterre J.
Published: April 2011

Background: Trastuzumab (T) is a very effective targeted therapy used in breast cancer patients but it can induce cardiac toxicity. Gene polymorphisms of Her 2 have been identified. According to a small report of Beauclair (2007), the polymorphism at codon 655 of the HER2 gene may represent a risk factor for cardiotoxicity induced by T. In this trial, we studied the incidence of the Val655Ile polymorphism in breast cancer patients with cardiac toxicity and in matched contol patients without cardiac toxicity.

Patients and methods: In our institution, between January 1st, 2007 and April 15th, 2010, 26 patients developed cardiac toxicity potentially related to T and were referred to a cardiologist and treated with angiotensinconverting enzyme inhibitors, Beta-blockers. Their cardiac function was monitored. Twenty two control pts without cardiac toxicity were matched according to age, received dose of anthracyclin, BMI, cardiac risk factors, cardiac treatment and initial left ventricular ejection fraction. Her2 gene polymorphism in codon 655 was studied by PCR on lymphocyte DNA from blood samples in both populations. Genomic DNA was extracted from EDTA blood samples (300μl) on the MagNa Pure Compact instrument (Roche Diagnostics, Meylan, France), using the MagNA Pure Compact Nucleic Acid Isolation Kit according to the manufacturer's instructions. The HER2 Ile655Val (rs1163201) polymorphism was detected by sequencing using a 3730 DNA Analyzer (Applied Biosystems, Courtaboeuf, France) with the BigDye Terminator Cycle Sequencing kit and universal primers M13.

Results: The mean age was 54.5 (31-72) and 52.5 (37-73) years respectively in the cardiac toxicity group and in the control group. In the cardiac toxicity group, 17 patients were in an adjuvant or a neoadjuvant setting, 9 were treated for a metastatic disease; 7 had cardiac risk factors (hypertension, diabetes, dyslipidemia or cardiac familial event). The control pts had similar characteristics. In the cardiac toxicity group 3.9% (1 patient) presented a genotype Val/Val at Her 2 codon 655, 42.3% (11)were heterozygous Ile and 53.8% (14) had the wild type. In the control population, the incidence was respectively 4.5% (1 patient), 31.8% (7) and 63.7% (14). No differences were found between the both groups. Discussion-Conclusion: The incidence of mutated, heterogeneous and wild type genotype was similar as the in the literature. We could not confirm the cardiac risk related to the Val allele at Her2 codon 655. Her2 polymorphism cannot be used in clinical practice to predict the risk of cardiac toxicity of Trastuzumab.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-11.
Abstract P3-14-12: High Risk of Recurrence in Japanese Patients with HER2-Positive T1N0 Breast Cancer
Authors: Tanaka K , Kawaguchi H , Koga C , Nishimura S , Yoshiyama T , Yamaguchi H , Nakamura Y , Ohno S.
Published: April 2011

Background: The necessity of adjuvant trastuzumab therapy for patients with T1N0M0 tumors remains controversial. The objective of this study is to determine the risk of recurrence in Japanese women with T1N0 HER2- positive tumors compared with HER2-negative tumors. Methods: Among 1,180 patients with breast cancers diagnosed at our institution between 2001 and 2007, we reviewed 464 T1N0M0 diseases in which HER2 status was evaluated by IHC or gene amplification, who had not received trastuzumab in the adjuvant setting. Recurrence free survival (RFS) was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were used to determine the association of each group with the risk of recurrence. Results: Seventy-nine (17%) of 464 patients had HER2-positive tumors and remaining 385 (83%) were HER2-negative diseases. Patients who had HER2-positive tumors tended to be younger (P=0.015), have more hormone receptor-negative tumors (P<0.001), and have higher histological grade (P<0.001). At a median follow-up of 46 months, 18 patients had experienced recurrences. The 5-year recurrence-free survival (RFS) rates were 88.2% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P<0.001). In patients with T1bN0 tumors and T1cN0 tumors, HER2-positive group had worse RFS than HER2-negative group (P=0.004 and P=0.002, respectively), while there were no differences in the RFS between patients with T1aN0 HER2-positive and HER2-negative tumors (P=0.835). In a multivariate analysis, HER2 status was identified as one of the independent risk factors to predict RFS in patients with T1N0M0 breast cancers (hazard ratio 5.23; 95% CI, 2.07 to 13.21; P<0.001). Conclusion: Japanese women with T1bcN0M0 HER2-positive breast cancer have a significant high risk of recurrence, and adjuvant trastuzmab therapy should be considered for those patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-12.
Abstract P3-14-13: Necessity of Confirming the Biological Marker of Distant Metastatic Lesion for Breast Cancer Patients
Authors: Nakamura R , Yamamoto N , Fushimi K , Iwase T , Itami M , Miyazaki M.
Published: April 2011

Background

The systemic management of metastatic breast cancer patients is usually based on biological marker of the primary tumor. However, characteristics of hormone status or HER2 over expression may change with metastatic site due to long term treatment for metastatic cancer with endocrine therapy, chemotherapy or biologic agents. The first purpose of this study was to investigate the concordance in HER2 over expression between primary tumor and distant metastases. The second purpose was to evaluate the efficacy of biologic agents for the patients with positive changes in HER2 status.

Material and methods One hundred forty-one patients had biopsy or operation of their metastatic site from 2000 to December 2009 at the Chiba Cancer Center Hospital. Specimen of operation or biopsies of suspected metastatic site were obtained from breast cancer patients. Specimen were analyzed pathologically to confirm metastatic disease and secondly to evaluate

HER2 by immunohistochemistry or FISH.

Results

Specimen of metastatic site were 67 local lesion (breast or lymph node), 27 brain, 16 liver, 12 bone and 5 others organs (stomach, intestine, ovary or uterus. Negative, positive or no change in HER2 status was observed in 4%, 6%, and 90% respectively. Positive changes of HER2 in metastatic site were 3(4%) local lesion, 3(11%) brain, 1 (7%) lung, 0(0%) liver, 2(17%) bone, and 0(0%) others, respectively. Three patients with positive change in HER2 status of metastatic site were treated to trastuzumab. Two of 3 patients with HER2 positive change were assessed to responded to trastuzumab-based treatment schedules.

Conclusions This study demonstrates the presence of substantial discordance in HER2 overexpression between primary tumor and metastases site.Metastatic tissue confirmation might be considered in patients with suspicious metastatic recurrence or resistance trastuzumab treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-13.
Abstract P3-15-06: No Correlation between Endocrine Symptoms and Musculoskeletal Symptoms in Women Receiving Adjuvant Aromatase Inhibitor Therapy
Authors: Cigler T , Singer O , Moore A , Chuang E , Vahdat L , Reichman B , Levine AB , Do HT , Mandl LA.
Published: April 2011

Background:

The etiology of Aromatase Inhibitor (AI) associated musculoskeletal symptoms remains unclear. It has been proposed that musculoskeletal side effects are related to the estrogen depletion achieved on AI therapy. Estrogen depletion with AI therapy is known to result in endocrine side effects. The 18-item Functional Assessment of Cancer Therapy Breast Cancer-Endocrine Subscale (FACTB-ES) is a reliable and well validated quality of life questionnaire shown to be sensitive to changes in endocrine symptoms in breast cancer patients. The objective of this study was to determine whether among women with breast cancer treated with adjuvant AI therapy, self reported musculoskeletal side effects correlate with increased hormonal side effects as measured by the FACTB-ES. Methods:

In this 6 month, single center, prospective cohort study, post-menopausal women with hormone-sensitive, non-metastatic breast cancer prescribed AIs by their treating oncologist were evaluated by a rheumatologist at baseline (before starting the AI) and at 6 months. Women who reported new or worsening musculoskeletal symptoms since starting the AI were classified as symptomatic. The FACTB-ES was administered at each visit.

Changes in scores between baseline and 6 months were compared between

the symptomatic and asymptomatic groups

Results:

Thirty-five subjects completed the 6 month follow up period. Nineteen (54%) were symptomatic and n=2 (5.7%) discontinued the AI due to these musculoskeletal symptoms. Mean time to onset of symptoms was 6 weeks (range 2 to 18 weeks). Baseline characteristics including age, ethnicity and body mass index did not differ between the groups. There was no significant difference in hormonal symptoms between groups. Both groups had equivalent worsening of their endocrine symptoms as seen by the reduction in their FACTB-score. The mean change in FACTB-ES score was -2.52 (range: -31.00, 23.00) in the symptomatic women versus -2.06 (range: -19.00, 22.21) in the asymptomatic women (Wilcoxon rank sum p=0.95). Conclusions:

These data suggest that endocrine symptoms as measured by the FACTB-ES do not correlate with the development of musculoskeletal pain in women treated with adjuvant AI therapy for breast cancer. Though larger studies are necessary to confirm these results, the musculoskeletal symptoms associated with AI use may not be estrogen-dependent.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-06.
Abstract P4-02-07: A Progesterone Receptor Modulator, CDB-4124, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation In Vitro and In Vivo
Authors: Wiehle RD , Lantvit DD , Yamada T , Christov K.
Published: April 2011

CDB-4124 (Proellex or Telapristone acetate) is a modulator of progesterone receptor (PR) signaling which has been employed in preclinical studies for the treatment of uterine fibroids and endometriosis. Here we provide evidence for its action in breast cancer from both in vitro and in vivo studies. When CDB-4124 is given to rats at 200 mg/kg for 24 months it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. In a second set of experiments, we found that CDB-4124, given as subcutaneous pellets at two different dose suppressed MNU-induced mammary carcinogenesis in rats in a dose dependent manner (see table below). The high dose (30 mg over 84 days) increased tumor latency from 66 to 87 days (P<0.02), decreased incidence from 85% to 35% (P<0.01), and multiplicity, from 3.0 to 1.1 tumors/animal (P<0.01). Tumor burden (total of all tumor weights in an animal) decreased from 2.6 g to 0.26 g/animal (P<0.01). Moreover in suport of our observations, CDB-4124 significantly suppressed Ki-67 positive cells from 30.5±7.1% in placebo-treated to 25.4±14.4% in low-dose and further to 10.3±4.5% (P<0.001) in the high-dose treated animals.

CDB-4124 increased latency and inhibited the incidence, multiplicity and burden of mammary tumors

CDB-4124 inhibited cell proliferation and induced apoptosis in these mammary tumors and this correlated with decreased proportion of PR+ tumor cells. Serum progesterone was lowered but there were no effects on estradiol. This progesterone receptor modulator appears to exert its effects in the presence of estrogen. In a mechanistic study employing human T47D breast cancer cells we found that CDB-4124 suppressed G1/0-S transition by inhibiting cdk-2 and cdk-4 expression and this correlated with inhibition of ER expression. Taken together, these data indicates that CDB-4124 can suppress the development of spontaneous and carcinogen-induced ER+ mammary tumors in rats and thus newer progesterone receptor modulators may have implications for prevention and treatment of human breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-07.
Abstract P4-02-14: Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and a Validation
Authors: Yu K-D , Shao Z-M
Published: April 2011

Purpose

Previous studies have suggested that postmenopausal breast cancer women with wild-type CYP2D6 might actually have similar or superior recurrence free survival outcomes when they take tamoxifen rather than an aromatase inhibitor (AI). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.

Methods

We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive-metabolizer (EM) patients using annual hazard ratio (HR) data from BIG 1-98 trial. Then we replicated the model by evaluating 9-year event-free survival (EFS) using HR data from ATAC trial. We also employed two-way sensitivity analyses to explore the impacts of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates.

Results

The 5-year DFS of tamoxifen-treated EMs was 83.3%, similar to that for genotypically unselected patients receiving an AI (83.7%). In the validation study, we further demonstrated that EMs could get comparable survival benefit from tamoxifen relative to an AI (9-year-EFS, 81.4% vs. 83.2%). Two-way sensitivity analyses showed the robustness of results.

Conclusions

Our modeling analyses indicate that among EMs, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to scrutinize the value of CYP2D6 genotype in the selection of endocrine therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-14.
Abstract P4-02-18: Antiprogestins as Possible Therapeutic Agents for Breast Cancer Patients Showing a High Expression of the Progesterone Receptor Isoform A
Authors: Rojas PA , Sequeira G , Gonzalez P , Bagnati A , Urrutia A , Medel J , Martinez Vazquez P , Gass H , Lanari C.
Published: April 2011

Near 75 percent of breast cancer patients express progesterone (PR) and estrogen (ER) receptors and are potential candidates to receive an endocrine therapy. Most of the endocrine therapies available have been designed to target ER and there is not much information about PR as a therapeutic target for breast cancer treatment. However, extensive clinical and experimental evidence suggest that progestins are associated with the induction and maintenance of the neoplastic phenotype in the mammary gland. Moreover, different antiprogestins including ZK 98299, ZK 230211 and RU-486 proved to exert excellent therapeutic effects in murine mammary carcinomas from the MPA-breast cancer model which express high levels of PR with an increased PR-isoform A/PR-isoform B ratio (PR-A/PR-B) (Lanari C et al, Endocrine Related Cancer, 2009 Feb, Jun;16(2):333-50).

The main goal of this study is to validate these experimental results using human breast cancer samples and to identify breast cancer patients that might benefit from an antiprogestin therapy. In the first part of this study our aim was to set up primary cultures from each breast cancer sample and to evaluate the in vitro response to antiprogestins, correlating this response with the PR-A/PR-B ratio. Tumor samples were obtained at surgery from patients diagnosed with breast cancer at the Magdalena V. de Martinez Hospital from General Pacheco and at the Rivadavia Hospital of Buenos Aires after signing the informed consent (n=70; median age 53.9 years). All tumor samples were processed by mechanical and enzymatic disaggregation and epithelial cells were purified by differential sedimentation techniques. Only 10 percent of the tumor samples succeeded in tissue culture and could be subcultured for further studies in 24 well plates. Cells were grown in culture medium in the presence of 10% fetal calf serum with or without RU-486 (10-8 M) or Tamoxifen (10-8 M). After one week of treatment, the cells were trypsinized and the total number of cells in each well was counted. Treatment with RU-486 or with Tamoxifen induced a decrease in the number of cells as compared to the controls (n=4, P<0.05). In these patients PR-A expression was the same or higher than PR-B as observed by Western Blot. Our results suggest that RU-486 might be an alternative therapy to treat breast carcinomas showing a high expression of PR-A. We still need more successful cultures in order to correlate the in vitro responsiveness with the PR isoform ratio.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-18.
Abstract P4-03-01: Inhibition of Fatty Acid Synthase (FASN) Sensitizes Breast Cancer Cells to Chemotherapy and Disrupts the Lipid Rafts
Authors: Espinoza I , Cheol Hong P , Busby R , Ruth L.
Published: April 2011

MN

Background: Breast cancer is the second leading cause of cancer death of women worldwide. One of the major challenges for a better prognosis of breast cancer patients is the ineffectiveness of chemotherapy and drug resistance. To investigate the mechanisms of drug resistance, resistant cancer cell lines have been established with various anticancer agents. We found that FASN, an important metabolic enzyme overexpressed in aggressive carcinomas, is t responsible in part for the drug resistance phenotype of breast cancer cells. Our findings show that blockage of FASN augments the cytotoxicity of the anti-mitotic drug Taxol in breast cancer cells. Moreover, C75 and Taxol have a synergistic effect both drugs are combined. The in vivo effect of C75 and Taxol and the mechanism by which blockage of FASN sensitizes the cells to chemotherapy are unknown. Material and Methods: In this study first we show the effect of C75 plus Taxol in breast tumor growth. BT474 cells were injected into the mammary fat pad of nude mice to generate the tumors. When the tumors were measurable we treated the mice with C75, Taxol or with a combination of both drugs. Second we studied the lipid rafts disruption after treatments by sucrose gradient and immunofluorescence. Results: We found that C75 plus Taxol extensively inhibited the tumor growth 9 fold and reduced the tumor size in 4 fold comparedn to the control mice (no treatement). In comparison C75 alone reduced the tumor growth in 1.5 fold only; and Taxol 2.5 fold compared to the control mice. These results show for first time that blockage of FASN (with C75) sensitizes breast cancer tumors to Taxol treatment in vivo. In addition, we studied the possible mechanism involved in the sensitization of breast cancer cells to Taxol by FASN blockage. Previous studies reported that blockage of FASN or Taxol treatment decrease the sphingolipids synthesis. Sphingolipids and cholesterol are the most abundant fatty acid in the lipid rafts in the plasma membrane. Disruption of lipid rafts has been shown to induce apoptosis in different carcinoma cell lines. Based in these findings, we studied lipid rafts in BT474 cells treated with C75, Taxol or combination of both with sucrose gradient and immunofluorescence microscopy. Discussion: Our results show that C75 and Taxol disrupt the lipid rafts. Thesefindings show that FASN is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-01.
Abstract P4-03-03: Lower Vitamin D Levels Are Highly Prevalent in Women with Breast Cancer
Authors: Li SP , Moule RN , Seah M-L , Rainbow S , Bhatti R , Steer KA , Windmill E , Makris A.
Published: April 2011

Purpose: The objectives of this study were to determine the prevalence of vitamin D insufficiency or deficiency as measured by serum 25-hydroxyvitamin D (25-OHD) in women with breast cancer and relate this to age, ethnic group, disease stage, and seasonal variation. Methods: Levels of serum 25-OHD were requested on blood samples collected from 129 female patients with histologically-proven breast cancer (median age 61 years; range, 30-88). Vitamin D deficiency was defined as serum 25-OHD less than 12.5 nmol/L, insufficiency as 12.5 to 50 nmol/L, and sufficient levels as greater than 50 nmol/L. The prevalence of inadequate (insufficient or deficient) vitamin D levels and median 25-OHD values were calculated for the cohort as a whole and analysed according to age, ethnicity (Asian (Indian/Pakistani), White and other), disease stage (early versus metastatic), and seasons. Statistical analysis was performed using non-parametric methods and a significance level set at a two-tailed p-value < 0.05.

Results: Overall 52% of women had inadequate levels of 25-OHD (45% deficient, 7% insufficient; median 29 nmol/L). There was no relationship with age. Lower levels were more common in Asian women (n=56) (64%; 16% deficient, 48% insufficient) compared with white women (n=65) (40%; all insufficient) and other (n=8) (62.5%; all insufficient). 25-OHD levels were significantly lower overall in Asian women in comparison with white women (median 36.5 versus 60 nmol/L; p=0.0002). When disease stage was considered, 54% of women with early breast cancer had inadequate 25-OHD levels (n=103) (7% deficient, 47% insufficient) in comparison with 42% of women with metastatic disease (n=26) (8% deficient, 34% insufficient) although overall levels were not significantly different between groups. There was no seasonal variation in 25-OHD levels.

Conclusion: The prevalence of insufficient or deficient vitamin D levels as assessed by 25-OHD in women with breast cancer, especially in the Asian population, is high. Our findings suggest that all patients with breast cancer should have routine testing of vitamin D status and if appropriate, offered adequate vitamin D supplementation.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-03.
Abstract P4-03-04: Body Mass Index as a Predictive Factor of Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Bellet Ezquerra M , Perez Garcia JM , Muñoz Couselo E , SauraManich C , Gomez Pardo P , Vidal M , Argiles G , De Mattos L , Cortes Castan J , Baselga Torres J.
Published: April 2011

Background: Obesity has been associated with worse pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and overall outcome in breast cancer patients (pts). Our aim was to retrospectively evaluate body mass index (BMI) as a predictive factor of pCR to NACT in pts treated at our institution, taking into account tumor HER2 status and CT dose adjustment.

Pts and methods: Pts with invasive breast cancer who received NACT followed by surgery at Vall d'Hebron University Hospital from January 2004 to December 2008 were analyzed. Pts were categorized as normal/underweight (BMI < 25 kg/m2), overweight (BMI of 25 to < 30 kg/m2), and obese (BMI ≥30 kg/m2). The overweight and obese groups were combined (BMI-high) and then compared with the normal/underweight group. Univariate and multivariate analyses were performed to assess the association between BMI and pCR (no invasive tumor in breast and nodes).

Results: 256 consecutive pts were included. Median age was 52.5 years. According to BMI, 38.7% were normal/underweight and 59.4% were BMI-high. 23.4% of the pts had HER2 positive tumors (n=60), 84% received anthracyclines-and taxanes-based CT, and 46.6% of the HER2 positive pts were treated with trastuzumab. Drug dose was reduced in only five pts with a body surface area > 2m2. No statistically significant association was found between BMI and any tumor characteristics. In the univariate analysis, BMI-high was associated with worse pCR in the whole population (p=0.017), as well as in HER2 positive pts (p=0.013). In the multivariate analysis, BMI did not significantly predict pCR in the total population, although a trend was observed (p=0.098). In the HER2 positive subgroup, however, BMI was an independent predictive factor of pCR (p=0.001). Among luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 < 20% and histological grade 1 or 2)], luminal B [estrogen receptor positive and/or progesterone receptor positive and (Ki67 ≥20% or histological grade 3)], and triple negative tumors, BMI was not a predictive factor of pCR.

Conclusions: Our results suggest that higher BMI is likely associated with worse pCR, particularly in HER2 positive pts. A better understanding of the molecular links between obesity and breast cancer is necessary to identify new predictive factors of pCR to NACT.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-04.