bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-13-06: Seasonal variation in onset of inflammatory breast cancer: Evidence of an infectious trigger
Authors: Hashmi S , Liu Y , Bethony J , Cristofanilli M , Levine PH
Published: August 2014

Introduction:

Inflammatory breast cancer (IBC) is a rare but extraordinarily aggressive disease with a number of studies indicating that environmental factors play the most important role. We have identified four reported clusters of IBC and our investigations thus far suggest that local toxic or infectious agents could be involved in the pathogenesis of the disease. IBC, like Burkitt's lymphoma (BL) has been reported to cluster and both have been implicated with infectious agents. Since BL has been reported to have a seasonal variation attributed to acute malaria symptoms as the precipitating agent, we decided to investigate the seasonality of IBC in two populations.

Methods:

For our analysis we used the datasets of two IBC referral groups. The first group consisted of a series of 163 consecutive cases of patients seen at Fox Chase Cancer Center (FCCC) almost all being from the Northeast U.S. (NE) and Canada. At the time of initial visit a detailed series of questions was specifically directed at identifying the accurate time of the first onset of symptoms/signs including skin rash, swelling, pain, nipple retraction and palpable mass. The second was the IBC registry (IBCR), established at the George Washington University with the purpose of collecting standardized clinical and epidemiologic data (including a detailed interview) and biospecimens from patients with IBC in the U.S and Canada. Complete data on patients in both groups were evaluated, including diagnostic workup, pathologic findings and treatment.

Results:

Of the 163 FCCC patients, 156 had the month of onset of symptoms clearly delineated. Of the 161 patients in the IBCR, 153 had month of symptomatic onset defined. In the combined groups, 181 NE patients were compared with 63 from the South. A seasonal pattern was noted in the NE patients, a bimodal pattern showing most patients with onset in March and July-Sept. No seasonal pattern was noted in patients from the South.

Conclusion:

The reports of IBC clusters are consistent with an acute triggering factor, possibly an infection. The seasonality we observed in NE patients but not in southern patients is consistent with this hypothesis. We are currently continuing to investigate clusters of IBC and are testing for specific candidate infectious agents as well as candidate environmental toxic agents to further understand possible triggers for this disease.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-06.
Abstract P5-13-07: Genetic polymorphism of estrogen metabolizing enzyme CYP17A1 rs743572 impacts on serum testosterone level in Japanese premenopausal women
Authors: Yoshimoto N , Nishiyama T , Yamashita H , Takahashi S , Shiraki N , Sugiura H , Endo Y , Iwasa M , Asano T , Hato Y , Fujii Y , Toyama T
Published: August 2014

The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We recently demonstrated that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype, and we created risk prediction models for ER-positive breast cancer in both pre- and post- menopausal women using genetic factors (single nucleotide polymorphism (SNP)), environmental risk factors, serum hormones and growth factors by logistic regression analysis. Serum level of testosterone, which is the precursor of estradiol in estradiol synthesis, was found to be a risk predictor in both pre- and post- menopausal women. On the other hand, it has been reported that some SNPs, including those of estrogen-related genes such as ESR1 and CYP17A1, are correlated with breast cancer risk by genome-wide association studies. To acquire some insights into this mechanism, we analyzed genetic factors (14 SNPs), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3)) in 913 women with breast cancer and 278 disease-free controls for correlation between them.

Serum testosterone and prolactin levels were significantly higher in ER-positive breast cancer patients than in disease-free controls in both pre- (p<0.0001, p<0.0001) and post- (p<0.0001, p = 0.007) menopausal women, and serum estradiol level was significantly higher in ER-positive breast cancer patients than in disease-free controls only in premenopausal women (p = 0.0005). There were significant differences in serum hormone levels among the women with each SNP genotype (homozygotes of major allele, heterozygotes and homozygotes of minor allele), including testosterone among rs743572 genotype (p = 0.014), estradiol among rs827421 genotype (p = 0.016), IGF-1 among rs6905370 genotype (p = 0.032), and prolactin among rs1042522 genotype (p = 0.035) in premenopausal women, as well as estradiol among rs3803662 genotype (p = 0.027) and IGFBP3 among rs6905370 genotype (p = 0.036) in postmenopausal women. In particular, serum testosterone level was significantly different among the rs743572, which is one of the enzymes that convert testosterone to estradiol, of genotypes (AA: 0.308 +/- 0.180 ng/ml, AG: 0.319 +/- 0.193 ng/ml and GG: 0.380 +/- 0.187 ng/ml, p = 0.014). On the other hand, the rs743572 heterozygotes of CYP17A1 have been reported to have increased breast cancer risk than homozygotes of both the major allele and minor allele in premenopausal women. Further studies are required to clarify this mechanism.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-07.
Abstract P5-13-10: Quality of care for premenopausal patients with early-onset breast cancer in Germany
Authors: Fischer D , Hedderich M , Heinrich A , Wedel B , Banz-Jansen C , Rody A , Waldmann A
Published: August 2014

Background and objective: The objective of the study is to evaluate how young breast cancer patients between 2002 and 2011 are treated adjuvantly and whether treatment adheres to the guidelines. The distinction between this cohort and a normally distributed cohort was verified.

Materials and methods: The study evaluates the data from a total of 2500 patients who were treated adjuvantly in the period from 2002 until 2011 and participated in a resident mother-child program. Until now, the data of 1053 patients have been analyzed. In cohort I (date of diagnose: 2002 - 2006) 535 women were analyzed, in cohort II (date of diagnose: 2010-2011) 518. The data includes TNM-stage, the biology of tumor, therapies and their guideline-adherence. In addition the amount of participation in studies was evaluated. All data were compared to an age-heterogeneous cohort from the state of Schleswig-Holstein and the DMP- report of the state of North Rhine-Westphalia (“older group”).

Results: The median age of the cohort I and II was 39 years. The median age of the age-heterogeneous groups was 59 years. 53% were diagnosed with stage pT1, 37% pT2, 7% pT3 or pT4. 49% of the patients in cohort I were pN0 (cohort II 58%), 31% pN1 (cohort II: 28%) and 20% (cohort II: 14%) had a more intense infestation of lymph nodes. The size of the tumors and the involvement of the lymph nodes were significant higher in the younger patients as in the older patients.

44% of the tumors showed G3, 34% were ER negative, 36% PR negative and 76% Her2 negative. 23% of the patients showed a triple negative carcinoma. The tumor biology was also worse in the younger patients than in the age-heterogeneous group.

All in all in cohort I 47% of the patients underwent mastectomie (cohort II:37%, older patients: 29%). 59% of the patients in cohort I with stage pT1 underwent breast-conserving surgery (cohort II: 69%, older group: 82%). Overall 15% of the women in cohort I received mastectomy with subsequent reconstruction (cohort II: 17%, older patients: 7%). 25% of the patients in cohort I received sentinel node biopsy only (cohort II 48%), 90% of the young patients received chemotherapy (older patients 59%), overall 21% of them were treated within studies. 51% of the young patients with antiendocrine therapy received GnRH-analoga, in the age of 40 years or younger 41%. The examination with regard to the conformity with guidelines showed a high guideline adherence in the younger group.

Conclusion: Young breast cancer patients provide a special challenge for the therapists because their prognosis is often worse because of a larger tumor and more metastatic lymph nodes as well as the worse tumor biology. They get a more aggressive therapy analogue to their worse situation. The therapies have a high guidelines adherence.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-10.
Abstract P5-14-06: Outcomes in 500 patients from a large, retrospective study of APBI with a strut-based breast brachytherapy applicator
Authors: Yashar C , Butler E , Einck JP , Finkelstein SE , Graves YJ , Han B , Hong RL , Komarnicky LT , Lyden M , Mahalingam SB , Mantz CA , Nasr N , Nigh SS , Pollock J , Reiff JE , Scanderbeg D , Snyder MR , Strasser JF , Kuske RR
Published: August 2014

Purpose/Objectives:

The SAVI Collaborative Research Group (SCRG) is a coalition of 14 institutions who have retrospectively compiled a large database of APBI patients treated with a strut-based brachytherapy device (SAVI). This report details the findings of statistical correlations between numerous dosimetric variables and cosmetic outcome.

Materials/Methods:

The SCRG study enrolled 1005 patients. A subset of patients with complete dosimetry and more than 1 year of follow-up by a radiation oncologist were analyzed for toxicity, cosmesis and recurrence/survival. Dosimetric parameters were tabulated for patients, including: V90, V95, V100, V150, V200, skin spacing (skin-bridge), maximum skin dose, tumor size, PTV-Eval volume and applicator size (model). Toxicity (e.g., telangiectasia, fibrosis, fat necrosis, seroma) were graded by physicians for patients with at least 1 year of follow-up (up to 6 years) using the CTCAE v3 Scale and fat necrosis using a simplified CTCAE scale (Grade 1 asymptomatic but seen on imaging, grade 2 symptomatic without intervention, & grade 3 required intervention).

Results:

Median follow up in this cohort was 29.2 months (range 2.4 to 72.2 months). Follow up was >2 yr and >3 yr for 323 and 191 subjects, respectively. Overall, in 500 subjects the late toxicity (grade ≥2) rates were less than 5% during follow up: telangiectasia 1.0%, fibrosis 4.1%, seroma 2.9% and fat necrosis 0.6%. Cosmesis was reported at various post-APBI follow-up visits following treatment completion (6, 12, 24, 36, 48 & 60+ months). For the 6 and 12 month intervals, 98% (n = 122) and 97% (n = 262) were reported excellent or good (E/G), respectively. At 24, 36, 48 and 60 month intervals, the E/G rates were 93% (n = 184), 90% (n = 98), 100% (n = 41) and 94% (n = 15), respectively. The raw rates of ipsilateral breast tumor recurrence (IBTR) and TR/MM were 1.6% (n = 8) and 1.2% (n = 6), respectively, in 500 patients with >1 year of follow up. The 1- and 2-year actuarial rates of overall survival and disease-free survival were: 1-year, 99.6% & 99.4%, resp. and 2-year, 99.2% & 96.7%.

Conclusions:

APBI treatment with the strut-based applicators was well-tolerated, demonstrated low toxicity rates, favorable cosmetic outcomes and excellent local control over the follow-up to date. Patients with challenging breast anatomy were successfully treated with strut-based devices.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-06.
Abstract P5-14-17: Post-lumpectomy tumorbed delineation for breast boost or partial breast irradiation: The influence of additional MRI and CT imaging
Authors: den Hartogh MD , Philippens MEP , van Dam IE , Kleynen CE , Tersteeg RJHA , Kotte ANTJ , van Vulpen M , van Asselen B , van den Bongard DHJG
Published: August 2014

Rationale/Purpose

In early stage breast cancer patients, most recurrences occur in the vicinity of the original tumor location. Therefore, after initial lumpectomy it is important to accurately delineate the tumorbed (TB) area for breast boost and partial breast irradiation on the planning-CT scan. However, consistency in TB delineation among radiation oncologists is low on standard CT imaging.

The purpose of this study was to determine whether additional pre- and postoperative MRI and CT imaging could increase consistency in standard CT-guided target volume delineation among radiation oncologists.

Methods

Fourteen cT1-2 patients underwent MRI and CT imaging in supine radiotherapy position before and after lumpectomy. TBs were delineated by 4 breast radiation oncologists following delineation guidelines on the standard postoperative planning-CT alone, and planning-CT registered to 1) postoperative MRI (T1 (with and without fat suppression) and T2 weighted sequences) 2) preoperative contrast-enhanced (CE) CT, and 3) preoperative CE-MRI (T1 weighted sequence with fat suppression). Consistency was defined by the conformity index (CI), which was calculated by dividing the encompassing volume of each observer pair, by the volume of overlap for each observer pair. Furthermore, volumes and the distance between centres of mass (dCOM) of the delineated TBs were determined. A Wilcoxon signed-rank test was performed to compare variables between different imaging modalities, with a significance level of a = 0.05.

Results

Results of the analysis are shown in Table 1. Addition of a postoperative MRI to the standard postoperative planning CT did not influence the CI (p = 0.176) or dCOM (p = 0.110). However, the TB volumes increased significantly with a median increase of 6 cm3 (p<0.001). Addition of a preoperative CT or MRI increased the CI by 0.01 and 0.02 (both p<0.001). Furthermore, preoperative CT and MRI increased dCOM (p = 0.004 and p = 0.001) and volumes (both p<0.001).

Table 1 medianrange  p-valueVolume (cm3)     CT224-934 CT + postoperative MRI283-964<0.001CT + preoperative CT266-933<0.001CT + preoperative MRI257-933<0.001      Conformity index     CT0.570.00-0.90 CT + postoperative MRI0.610.00-0.890.176CT + preoperative CT0.580.00-0.90<0.001CT + preoperative MRI0.590.00-0.89<0.001      dCOM (mm)     CT50-53 CT + postoperative MRI40-520.110CT + preoperative CT31-420.004CT + preoperative MRI50-480.001

Conclusion

Although significant, the addition of postoperative MRI, preoperative CE-CT or preoperative CE-MRI did not result in a clinically relevant improvement of the consistency in postoperative CT-guided TB delineation among radiation oncologists. Furthermore, target volumes increased with all imaging modalities.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-17.
Abstract P6-01-02: Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling
Authors: Mandal M , Prasanth Kumar BN
Published: August 2014

Background

Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs.

Methods

The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed.

Results

Here, we elucidated how the combination of TAM and the selective COX-2 inhibitor, celecoxib (CXB) at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1a activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment.

Conclusions

Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive combination of TAM and CXB is a potential drug candidate treatment for breast tumors expressing high levels of VEGF and VEGFR2. This ingenious combination might be a better tailored clinical regimen than TAM alone for breast cancer treatment.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-01-02.
Abstract P6-04-16: TGF-b2, a novel target of CD44-promoted breast cancer invasion
Authors: Al-Riyami H , Madani S , Gupta I , Shanmuganathan S , Abdraboh ME , Al-Farsi Y , Raj MHG , Ouhtit A
Published: August 2014

Hyaluronan (HA) mediates communication between cancer cells and the environment via interactions with the cell surface receptor CD44. We have previously shown that CD44-HA interaction in BC cells promotes adhesion to bone marrow endothelial cells. This suggests that HA/CD44 signalling may be correlated with breast cancer (BC) metastasis. The long-term objective of this study is to increase our understanding of the mechanisms by which CD44-HA interaction promotes BC metastasis, and further identify and validate CD44-downstream transcriptional targets for anti-metastatic therapy.

Pursuant to this goal, we have developed a tetracycline (tet)-regulated expression of CD44 gene in the BC cell line MCF-7 (B5 clone) and identified TGF-beta2 (Transforming Growth Factor beta-2; 3 fold induction) as a potential CD44s-downstream transcriptional target by microarray analysis. To further validate this finding, the same RNA samples, used for microarray analysis and their corresponding protein lysates collected from the BC cell line MCF-7-B5, were examined for CD44 expression in the presence of HA for 18, 24, and 48 hr post-tet withdrawal. Expression of TGF-beta 2 was examined using RT-PCR and western-Blot analyses.

Our results showed that TGF-beta2 mRNA levels were significantly elevated following the removal of tet at 18, 24, and 48 h post-HA stimulation compared to the parental cells. Furthermore, the TGF-beta2 precursor protein increased in a time-dependent pattern upon HA-stimulation and in the absence of tet. More interestingly, inhibition of CD44 gene by RNAi method decreased TGF-beta2 expression upon HA-stimulation and in the absence of tet.

Our data strongly support the hypothesis that TGF-beta2 is a potential target of HA/CD44- downstream-signaling mediating BC cell invasion. Ongoing investigation aims to elucidate the signal transduction pathways coupling CD44 to the regulation of TGF-beta2 expression, and further validate CD44/TGF-beta2 axes in breast tumor invasion and metastasis.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-16.
Abstract P6-05-21: High standardized uptake value of 18F-fluorodeoxy-glucose positron emission tomography is related with FOXM1 expression, which negatively influences survival in breast cancer patients
Authors: Ahn SG , Lee HM , Lee HW , Lee SA , Leem S-H , Jeong J , Chu I-S
Published: August 2014

Background

Standardized uptake value (SUV), which is an indicator reflecting glucose uptake in 18F-fluorodeoxy-glucose positron emission tomography (18FDG-PET), can be implicated to be a prognostic factor in various malignant tumors. Using a data set with gene expression profiling, we tried to uncover a molecular marker associated with a high SUV, along with an exploration its prognostic value in breast cancer.

Methods

Microarray gene expression profiling was performed in 287 breast tumor samples. Five hundred nanograms of total RNA were used for labeling and hybridization, according to the manufacturer's protocols (Illumina, San Diego, CA). In 66 samples with SUV, genes with expression patterns highly correlated with the value of SUV were selected for cluster analysis. Five hundred thirty tree gene features were selected for analysis. Patients were divided into the following two groups: SUV-high cluster and SUV-low cluster. Hierarchical clustering analysis based on 533 gene features. The prognostic value of the identified gene was validated in 287 samples and the online public set.

Results

Gene network analysis using Ingenuity Pathway Analysis software revealed considerable enrichment of the gene network toward FOXM1 in the SUV-high cluster, suggesting that its activation might be a key determinant associated with SUV level. Also, the expression of many marker genes for cell proliferation, such as AURKA, AURKB, BIRC5, BUB1, and TOP2A, was significantly higher in the SUV-high cluster than in the SUV-low cluster. Next, in the 287 patients with known FOXM1 expression levels, the Kaplan-Meier survival analysis revealed a negative prognostic impact of highly expressed FOXM1 for overall survival (OS), disease-free survival (DFS), and distant-metastasis-free survival (DMFS) (P = 0.002, P = 0.015, P = 0.008, respectively; Table 1). To validate a prognostic impact of FOXM1 in an external data, we performed a survival analysis using online gene-expression array data. There was significant correlation between the FOXM1 expression level and OS, DFS and DMFS.

Conclusion

Here we analyzed FOXM1 as a biomarker associated with a high SUV and demonstrated that FOXM1 is a negative prognostic factor in breast cancer.

Prognostic significance of FOXM1 in 287 patients Overall SurvivalBreast cancer-specific survivalDisease-free survivalDistant metastasis-free survivalFOXM1 high (n = 144)log-rank testlog-rank testlog-rank testlog-rank testFOXM1 low (n = 133)P = 0.002P = 0.001P = 0.015P = 0.008

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-21.
Abstract P6-06-15: Cost impact of oncotype Dx® breast cancer assay use in a fully integrated healthcare delivery system
Authors: Carlson JJ , Watanabe J , Boudreau D
Published: August 2014

Background:

The Oncotype Dx Breast Cancer Assay (ODX) provides relevant information on the risk of distant recurrence and the treatment effect for adjuvant chemotherapy (ACT) in early stage breast cancer. However, no studies to date have evaluated the impact of ODX use on total and oncology specific costs. The objective of this study was to explore the impact of ODX use on total and oncology specific costs within the Group Health Cooperative health plan.

Methods:

Our study sample included women diagnosed between 2004-2012 with ER positive, node negative, early stage (I, IIA, or IIB) breast cancer. Data were collected from SEER and automated health plan data. We used multiple logistic regression to model receipt of adjuvant chemotherapy as a function of OncotypeDx Breast Cancer Assay receipt. Further, we used multiple linear regression to model total and oncology specific one-year costs as a function of OncotypeDx Breast Cancer Assay receipt. In both analyses, we adjusted for key patient, tumor, and health system factors.

Results: The study population consisted of 1510 women, 13% of which received the ODX test. The groups were similar across relevant clinical and demographic characteristics with the exception of age at diagnosis, stage, tumor grade and drug benefits. In the logistic regression analysis, patients who received ODX were 51% less likely to receive adjuvant chemotherapy versus those who did not receive the test. In the multiple linear regression analysis, those who received ODX had fewer total and oncology specific one-year costs (total costs difference: -$9,149 (95% CI: -$13,818, -$4,481, P-Value: <0.001); oncology specific cost difference: -$1,380 (95% CI: -$2,361, -$400, P-Value: <0.006).

Study Results ODX vs. No ODX95% CIP-valueTotal cost difference*-$9,149-$13,818 to -$4,481<0.000Oncology cost difference*-$1,380-$2,361 to -$4000.006Adjuvant chemotherapy use (OR)*0.490.33 to 0.73<0.000* Model covariates: stage, Charlson comorbidity score, age at diagnosis, tumor size, tumor grade, race, and pharmacy benefits

Conclusions: Our results are the first to report on the impact of the ODX test directly on total and oncology specific costs. In accordance with previous studies that used modeled cost estimates, i.e. through cost projections focusing solely on the adjuvant chemotherapy reductions, we found a statistically significant difference in both total and oncology specific costs. These data further bolster the evidence that suggests the ODX lowers total and oncology specific costs. Further evidence is needed to evaluate the impact of ODX on clinical outcomes.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-15.
Abstract P6-07-12: Should adjuvant zoledronic acid be used in early-stage, endocrine-sensitive breast cancer?
Authors: Lamond NWD , Skedgel C , Rayson D , Younis T
Published: August 2014

Introduction: Adjuvant zoledronic acid (ZA) appears to improve disease-free survival (DFS) in women with endocrine-sensitive breast cancer and low estrogen levels (LEL) including post-menopausal women, and pre-menopausal women treated with LHRH agonists. ZA, however, is also associated with potential adverse events and incremental drug acquisition costs. An overall assessment of the long-term clinical and economic impacts of adjuvant ZA may therefore help guide the decision to adopt this novel therapeutic option. We examined the incremental quality-adjusted life-years (QALY) and costs per QALY associated with adjuvant treatment including ZA relative to treatment without ZA in women with endocrine-sensitive breast cancer and LEL. Methods: A Markov model was developed to compute cumulative costs, from a Canadian perspective, and QALY associated with and without adjuvant ZA over a 25-year horizon. Costs, utilities, DFS and adverse events were derived from relevant clinical trials, the literature and local resources. One-way and probabilistic sensitivity analyses were conducted for key model parameters. Results: Adjuvant ZA was associated with incremental QALY gains of 0.62 and 0.42 and resultant CU estimates of $12,617 and $19,775 per QALY gained in pre- and post-menopausal women, respectively. CU estimates were robust across reasonable uncertainty ranges in all parameters. Conclusions: Adjuvant ZA appears to be associated with long-term QALY gains in women with endocrine-sensitive breast cancer and LEL as well as CU estimates that are below commonly accepted North American thresholds. The favourable long-term clinical and economic impacts observed in this study further support the use of adjuvant ZA in this setting.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-12.
Abstract P6-11-03: Follow up of breast cancer patients who underwent gamma knife radiosurgery for a diagnosis of brain metastases: A single institutional experience
Authors: Abu-Khalaf MM , Hatzis C , Chung G , DiGiovanna M , Tara S , Erin H , Lajos P , James YB , Veronica CL
Published: August 2014

Background: Breast cancer (BC) is the second most common cause of brain metastases in the United States. We performed a retrospective analysis of BC patients (pts) in the Yale Gamma Knife Radiosurgery (GKRS) database treated for brain metastases (mets) to report overall survival (OS) from time of GKRS, and to identify factors that predict improved survival outcomes.

Methods: We performed retrospective review of the Yale database of BC pts treated with standard GKRS technique for brain mets from 2000 to May 2013. Treatment doses typically ranged from 16 to 24 Gy prescribed to the 40-85% isodose surfaces. Overall survival (OS) for each patient was calculated from the date of first GKRS treatment of brain metastases. Variables included age, Karnofsky Performance Status (KPS), pre/post whole-brain radiation treatment (WBRT) and/or surgical resection, and # of brain mets treated (1-4 vs ≥5).

Results: A total of 80 BC pts were identified, with a mean age of 56.2 yrs; KPS 40-60 in 8pts (10%), 70-80 in 13 (16%), 90-100 in 41 (51%), unknown in 18 (23%); ER+ in 38 (48%), ER- in 38 (48%), unknown in 4 (5%); HER2 + in 38 (48%), HER2- in 33 (41%), indeterminate in 3 (4%) and unknown in 6 (8%). BC subtypes are Luminal A (ER+/HER2-) in 16 (20%), Luminal B (ER+/HER2+) in 19 (24%), HER-2(ER-/HER2+) in 17 (21%), Basal (ER-/HER2-) in 17 (21%), unknown in 11 (14%). Number of brain mets at time of first GKRS ≥5 in 32 (40%); prior WBRT in 30 (38%); WBRT post GKRS in 9 (11%); surgical resection for brain mets in 13 (16%) prior to GKRS and post GKRS in 9 (11%); 16% had ≥3 GKRS. Median time from primary BC dx to brain mets is 62.8 months (m) (range 46.2-81.6); with no significant difference among subtypes. Median OS from GKRS is 13.1 m (7.6-21.9); median OS from brain mets is 18.8 m (11.7-23.9). On univariate analysis, factors associated with significant improved OS from time of GKRS included HER-2 subtype (p = 0.005), KPS 90-100 (p = 0.008), good control of systemic disease (p = 0.017), pre (p = 0.041) and post GKRS surgical resection (p = 0.02). Age, pre or post WBRT, # of brain mets (1-4 vs. 5) were not significant predictors of OS from time of GKRS. In a multivariate Cox analysis (46 cases), HER-2 subtype remained a significant predictor of improved OS from time of GKRS; (HR) 0.26, 95%CI 0.08 to 0.8, p-value = 0.02. There was a trend in favor of surgical resection of brain mets pre GKRS (HR 0.14, 95% CI 0.02 to 1.15, p-value = 0.067

Conclusion: GKRS offers good local control for BC pts with brain mets, and is a reasonable option for pts with ≥5 brain mets. Our results show no associated survival benefit for administration of WBRT pre/post GKRS. HER-2 subtype is a significant predictor of improved survival in BC pts undergoing GKRS for brain mets.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-03.
Abstract P6-11-05: ANG4043, a brain-penetrant anti-HER2 mAb increases survival in mice bearing intracranial BT-474 breast tumor cells
Authors: Lachowicz JE , Demeule M , Regina A , Houle E , Tripathy S , Castaigne J-P
Published: August 2014

Background: Treatment options for metastatic brain tumors originating from HER2-positive breast disease are limited due to the inability of most anti-tumor agents to enter the brain. While the selectively permeable blood-brain barrier (BBB) restricts access of therapeutics such as mAbs to the brain, transcytosis of hormones, nutrients, and other homeostatic modulators is mediated by transporters and endogenous receptors such as the low density lipoprotein receptor-related protein 1 (LRP1). We have created a family of peptides (Angiopeps) that are recognized by LRP1 and enter the brain via receptor-mediated transcytosis. Using these proprietary Angiopeps, we have created novel, brain-penetrant Peptide-Drug Conjugates. An iterative process of linker selection and reaction condition optimization led to the discovery of ANG4043, a conjugate of the peptide Angiopep-2 (An2) and an anti-HER2 mAb similar to trastuzimab. This brain-penetrant An2-mAb conjugate, which displays HER2 binding affinity and in vitro anti-proliferative properties similar to that of the native mAb, was tested in a murine model of breast tumor brain metastases. Methods: Athymic nude mice were stereotactically implanted 1.5 mm anterior and 2.5 mm lateral to bregma with 1×106 BT-474 cells twelve days prior to initiation of drug treatment. Body weight and morbidity/mortality were monitored daily. Separate groups of mice received mAbs that were labeled with the fluorescent probe Cyto-750 to allow for near infrared in vivo imaging. Results: Median survival in the control group was 45 days, compared with 68 days and 80 days for the 5 mg/kg (p = 0.0005) and 15 mg/kg (p = 0.0003) groups, respectively, demonstrating a 51% and 78% improvement over the control group. In addition, a greater degree of fluorescence was observed in intracranial BT-474 brain tumors in the ANG4043 group compared to the native anti-HER2 mAb group. Conclusions: These data demonstrate that ANG4043 reaches its target in brain tumors and increases survival in a mouse HER2-positive intracranial tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant anti-tumor therapeutics. We intend to progress this program to clinical stages both as monotherapy and in combination with ANG1005, the An2-paclitaxel conjugate that has shown encouraging results in clinical studies with primary brain tumors and breast cancer brain metastases.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-05.
Abstract P6-11-08: Risk of CNS relapse following adjuvant trastuzumab therapy – Updated literature-based meta-analysis
Authors: Mathew A , Brufsky AM
Published: August 2014

Background: Randomized trials of adjuvant trastuzumab in HER2-positive early breast cancer observed an increased risk for central nervous system (CNS) as site of first relapse. A meta-analysis of three trials with a total of 6752 patients followed up for a median of 2 years found an 82% increased risk for CNS relapse as first disease free survival (DFS) event with adjuvant trastuzumab use. It is thought that the greater risk for CNS as first relapse site is due to the lack of penetration of trastuzumab through the blood-brain barrier combined with better disease control in other visceral sites rather than the drug itself predisposing patients to CNS disease. Therefore, we hypothesize that the effect size of this association will decrease with increasing duration of follow-up.

Methods: A comprehensive literature search was performed. Updated results from the three randomized trials of adjuvant trastuzumab were identified. The NSABP B-31 and the NCCTG N9831 trials compared four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of Paclitaxel (T) with the same regimen combined with trastuzumab for a year. The HERA trial compared one or two years of adjuvant trastuzumab with observation. We abstracted the number of CNS relapse events in these trials and performed a meta-analysis with fixed-effect model using Mantel-Haenzel method.

Results: Out of a total of 7456 patients included in the analysis, CNS DFS events occurred in 98 patients receiving trastuzumab compared to 68 patients in the control group over a median follow-up period of 4 years. We found a 43% increased risk for CNS relapse as first DFS event in patients who received adjuvant trastuzumab compared to the group that did not receive the drug (RR 1.43; 95% confidence interval 1.06, 1.95). We found no inconsistency in risk ratio estimates between the three trials (I2 = 0%).

Discussion: Adjuvant trastuzumab is associated with a higher risk for CNS as first relapse site despite an increase in duration of follow-up. The reduction in effect size from the previously reported 82% increased risk observed with a 2 year follow-up period, to 43% with 4 years of follow-up adds to the body of evidence that the drug itself does not predispose a patient to CNS recurrence. On the contrary, the reduction in effect size could also be attributed to the crossover study design in HERA trial, where nearly 50% of patients in the control group eventually received trastuzumab. In summary, we propose that the adjuvant trials of the newer HER2 targeted therapy should be designed to look into CNS disease as not only first site of recurrence but also gather additional data on all CNS recurrences to further elucidate the mechanism of CNS disease with HER2 directed therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-08.
Abstract P6-11-10: Central nervous system metastases in breast cancer: Impact of tumour sub-type and outcome from current treatments
Authors: Chan A , O'Carrigan B , McGregor S , Beith J
Published: August 2014

Background: The use of more effective systemic therapies in the management of metastatic breast cancer has led to increased response rates, progression-free survival and overall survival. The incidence of central nervous system (CNS) metastases has become an increasingly important area of unmet need. It is important to identify tumour-related factors which may predict for CNS occurrence and assess the efficacy of treatments in current use.

Methods: Consecutive patients (pts) with breast cancer (BC) seen at 2 institutions following establishment of breast cancer databases were included: January 2000 (institution A) and January 2003 (institution B) to December 2012. Patient demographic data, tumour pathology and systemic treatment given were reviewed in those patients who developed CNS metastases. Multivariate analysis of factors impacting on overall survival in this patient population will be performed.

Results: Over the study period, 4751 pts with a median age of 52.7 yrs were seen, where 86.4% and 13.6% of pts presented with early and metastatic disease, respectively. In the entire population, 77% of tumours were hormone receptor positive, 21% HER2 positive, and 15% triple negative. Overall, 228 (4.8%) pts had CNS metastases with a median age of 48.9 yrs. CNS involvement was present at the time of first metastatic recurrence in 27% of pts who had CNS metastases. The proportion of pts developing CNS metastases according to tumour subtypes were: 48% hormone receptor positive, 36% Her2 positive, and 20% triple negative. Median time from diagnosis to development of CNS metastases (excluding pts with CNS involvement at the time of first metastatic disease) was 48.9 (4.7-248 months, m). The median time to development of CNS recurrence was 61m, 43m, 23m respectively, according to tumour subtype. CNS disease was parenchymal only, leptomeningeal only or both in 78%, 9%, 13% respectively. Pts who died from BC, had a median overall survival from initial BC diagnosis of 53.6m, whereas median overall survival from CNS metastases was 4.8 m. The impact of whole brain radiation with or without stereotactic therapy, surgical resection of brain metastases and type of systemic therapy administered following development of CNS disease on overall survival will be presented.

Discussion: CNS metastases occurred in up to 5% of breast cancer pts seen at two large cancer centres. Despite improvements in overall survival of metastatic BC pts with the use of more effective systemic treatments, the prognosis following CNS involvement remains extremely poor. Until specific interventions are available to manage CNS metastases in pts with breast cancer, it remains important to assess outcomes from current standard treatment in these pts.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-10.
Abstract PD3-5: Survival benefit conferred by the androgen receptor is lost in aromatase inhibitor treated breast cancer
Authors: Ali A , Bane F , Hao Y , McCartan D , O'Gaora P , Hill ADK , Young LS , McIlroy M
Published: August 2014

Aromatase Inhibitors have proven to be most effective in the treatment of post-menopausal breast cancer. Their mode of action is to inhibit the synthesis of estrogen (estrone) by the aromatase enzyme Cyp 19 thereby blocking ligand-dependent activation of the estrogen receptor. What has not been addressed to date is how cells that are deprived of estrogen, may potentially, adapt to the more androgenic environment resulting from long-term treatment with AI therapy. Research from our lab has identified the homeobox protein, HOXC11, to be an indicator of poor response to endocrine therapy and development of metastasis. To further our understanding of HOXC11 and its role in the development of endocrine-resistance and metastatic spread we undertook an RNA-seq experiment to identify its target genes in resistant breast cancer. This analysis identified PSAP, IFIT1 and HSP90AA1. Both PSAP (an androgen agonist) and HSP90AA1 (AR chaperone) are closely associated with AR which led to further investigation into the role of HOXC11 in the development of steroidal adaptability in Letrozole-resistant breast cancer. We hypothesize that HOXC11 regulated expression of PSAP results in oncogenic activation of AR in an AI resistant setting. Our findings have shown that AI-resistant cell lines in vitro have significantly elevated levels of AR and that loss of HOXC11 results in concommitant decrease in AR mRNA. In AI resistance expression of HOXC11 results in upregulation/stabilization of AR by PSAP thus enabling the tumour to adapt to use androgenic steroids for cell proliferation. The anti-androgen, Bicalutamide, reduces cell proliferation and cell motility in AI resistant cell lines. Survival analysis of AR in a TMA (n = 488) indicates that AR confers a survival benefit in the tamoxifen treated population. This protective effect is diminished in patients receiving AI therapy and is reflected in the altered Hazard Ratio of AR from the total population (HR: 0.485) to the AI treated cohort (HR: 1.197). Secreted PSAP was readily detectable in breast cancer patient serum and associates significantly with expression of HOXC11 in matched patient tissue (∼20). PSAP is associated with poor response to endocrine therapy and metastatic spread of prostate cancer and as it is secreted it could potentially be used to monitor patients on AI who might benefit from dual targeted therapy treatment.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-5.
Abstract PD3-7: Disease-free survival and Ki67 analysis of a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer (JONIE-1 study)
Authors: Miura D , Hasegawa Y , Horiguchi J , Ishikawa T , Hayashi M , Takao S , Kim SJ , Tanino H , Miyashita M , Konishi M , Shigeoka Y , Yamagami K , Kaise H , Akazawa K , Kohno N
Published: August 2014

Background:

Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We suggested that the addition of ZOL to neoadjuvant chemotherapy (CT) has potential anti-cancer benefit in postmenopausal patients with triple-negative breast cancer in JONIE-1 Trial (50% pCR rate in ZOL+CT: CTZ versus 0% in CT, p = 0.029). We analyzed the disease-free survival (DFS) as a secondary endpoint and baseline Ki67 levels between two groups.

Methods:

Women with Stage IIA-IIIB HER-2-negative breast cancer were randomly assigned 1:1 to CTZ group or CT group, CT was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles and ZOL 4mg was administered every 3-4 weeks. Among 188 patients recruited between March 2010 and April 2012 excluding 10 from the primary assessment, 178 patients were assessed. The aims of this study were to compare the relative efficacy or CTZ with the efficacy of CT in prolonging DFS in all patients and also to compare the pCR rates between baseline Ki67 high (20% and >20%) with Ki67 low (<20%) in ER positive cohort.

Results:

During a mean follow-up period of 34.4 months, breast cancer specific events (recurrence and death) occurred 17 participants, 7 in CTZ group and 10 in CT group. The 1-year, 2-year, and 3-year DFS rates were 97.7%, 88.4%, and 88.4% in CTZ versus 100%, 84.8%, and 81.1% in CT, respectively. In the ER positive cohort studied for Ki67 consist of 109 patients, 40 were in Ki67 low group and 69 were in Ki67 high group. Among Ki67 low group, number of pCR was none out of 18 in CTZ and 1 out of 22 in CT (p = .550). Among Ki high group, that was 6 out of 38 in CTZ and 3 out of 31 (p = .352).

Conclusion:

We could not find a modest improvement in disease-free survival compared the addition of ZOL to neoadjuvant CT with CT alone. Ki67 study for central analysis has been under investigation.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-7.
Abstract PD5-7: Phase Ib study of LCL161, an oral antagonist of inhibitor of apoptosis proteins, in combination with weekly paclitaxel in patients with advanced solid tumors: Safety and efficacy results, including breast cancer cohort
Authors: Dienstmann R , Adamo B , Vidal L , Dees EC , Chia S , Mayer EL , Baney TS , Dhuria S , Sen SK , Papoutsakis D , Cameron S , Infante JR
Published: August 2014

Background: LCL161 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing inhibitor of apoptosis proteins (IAPs). Preclinical studies demonstrated antitumor efficacy of LCL161 alone or in combination with chemotherapeutic agents, acting synergistically with paclitaxel in breast cancer models. A Phase I study confirmed potent pharmacodynamic (PD) effects at well-tolerated doses of 1800 mg once weekly. The purpose of this Phase Ib study was to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), safety, pharmacokinetics (PK), PD, and preliminary antitumor activity of LCL161 in combination with weekly paclitaxel.

Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week, immediately followed by escalating doses of LCL161 administered once weekly. PK and biomarker sampling was performed. Patients with breast or ovarian cancer were treated at the MTD/R2PD in the dose-expansion phase of the study.

Results: As of 4 June 2013, 61 patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 5), and 1800 mg (n = 48), including 26 patients with breast cancer and 19 patients with ovarian cancer. Median duration of exposure was 10 weeks. The most common LCL161-related adverse events (AEs) were diarrhea (53%), anemia (36%), and neutropenia (34%). Eleven patients experienced AEs indicated by the principal investigator as a toxicity requiring dose reduction or a change to a 3 week on/1 week off schedule (ten at 1800 mg and one at 1200 mg), seven of which were neutropenia or febrile neutropenia. The MTD was not reached, and 1800 mg was selected as the RP2D. In the safety expansion group of patients with breast cancer treated at 1800 mg, 17 (out of 20) patients were evaluable for response by investigator assessment using RECIST criteria; of these, 47% achieved a partial response, 35% had stable disease, and 18% developed progressive disease. Interestingly, responses were seen in patients with documented progression to prior taxane-based regimens. Of note, in the ovarian cancer cohort, one patient achieved a complete response. In the study overall, 26% achieved a partial response, and 30% experienced stable disease. No PK interaction between LCL161 and paclitaxel was observed.

Discussion: Combination therapy with LCL161 and paclitaxel is well tolerated, with manageable toxicities and encouraging clinical efficacy in breast cancer. Enrollment of additional patients with breast cancer resistant to paclitaxel is ongoing.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-7.