bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical testing using tumors from genetically engineered mouse mammary models
Authors: Varticovski L. , Hollingshead M. G. , Anver M. R. , Robles A. I. , Green J. E. , Hunter K. W. , Merlino G. , Nunez N. , Hursting S. D. , Steeg P. S. , Barrett C. J. 
Published: March 2020

10067 Background: Mouse models have been used extensively in preclinical testing of anticancer drugs. However, few of these models reflect the progression of human disease, and even fewer predict the performance of these drugs in clinical trials. Testing anticancer therapies in genetically engineered mouse (GEM) holds the promise of improving preclinical models and guiding the design of clinical trials. Unfortunately, the use of tumor-bearing GEM is hampered by the difficulty in simultaneously obtaining sufficient numbers of animals with the same stage of tumor development. The additional complexity in testing breast cancer therapies in the mouse is that all 10 mammary glands can develop tumors, frequently at different times. Methods: To circumvent the variable tumor latency and lack of synchrony in GEM, we transplanted tumor fragments or cell suspensions from multiple mammary tumor-bearing GEM into the mammary fat pad or subcutaneously into naïve syngeneic, immunodeficient athymic nude, or scid mice. Results: Tumors transplanted as fragments or cell suspensions derived from anterior mammary gland grew faster than the posterior tumors for serial passages without any significant morphologic differences. Cell suspensions using fresh or frozen cells were equally effective in generating tumors, and increasing the numbers of transplanted cells resulted in faster tumor growth. The transplantation strategy was reproducible in multiple breast cancer mouse models, including MMTV-PyMT, -Her2/neu, -wnt1/p53, BRCA1/p53, and others. Metastatic disease in the lungs was evident after removing the primary tumors at different rates for each mouse model. The transplanted primary tumors and the tumors arising in the original GEM had similar morphologic appearance and sensitivity to several chemotherapeutic and novel molecular targeted agents. Conclusions: We have established transplantable synchronous mammary tumors from GEM which also develop metastatic disease. These valuable mouse models are suitable for studying tumor-host interactions, tumor progression, and preclinical testing in a well-characterized molecular and genetic background. Testing these GEM tumors for conventional and novel molecular targeted therapies will be discussed. No significant financial relationships to disclose.
Initial results of a phase III study show safety of HRT and low dose tamoxifen
Authors: Bonanni B. , Santillo B. , Serrano D. , Veronesi U. , Rosselli Del Turco M. , Masullo P. , Monti N. , Andreoli C. , Decensi A. 
Published: March 2020

1009 Background: HRT is beneficial on menopausal disturbancies and decreased bone fracture risk and colorectal cancer (CRC), but increased VTE, cardiovascular events and breast cancer in the WHI trial. However, the WHI characteristics (median age 63.3 yrs, median BMI 28.5, use of oral HRT) diminish generalization of results. The WHI trial shows an increased BC risk, only with oral combined HRT. HRT and tamoxifen (T) was safe in subgroups of two prevention trials. T at low doses showed antiproliferative effects similar to the standard dose, without significant menopausal symptoms and endometrial proliferation. Methods: The HRT+T combination is being investigated in a multicentric, phase III trial in current or de novo HRT users, randomized to either T 5 mg/day or placebo for 5 yrs. The primary endpoint is the reduction of invasive and in situ BC. Results: Of 5,032 women contacted, 1,989 refused, 1,109 were not eligible, and 1,806 were enrolled in 46 centres. Median age is 53 years (33–72). BMI is <20 in 65.7%, <25 in 26.3%, >25 in 8.0%. Current or de novo users are 80.1% and 19.9%. In the former group, 45.9% use oral and 54.1% use TTS. Hysterectomized women are 389. Current users ≤3 years are 48.0%, 3–5 years 12.1%, >5 years 18.8%. 1256 women (74.2%) have at least one follow-up visit. Compared to baseline, most frequent side effects were: hot flashes (42.0% vs 35.0%), night sweating (39.0% vs 29.0%), anxiety/depression (41.0% vs 27.4%), vaginal dryness (29.2% vs 19.3%), headache (32.1% vs 25.1%), fluid retention (24.0% vs 19.0%). “Drop-outs” are 17.3%, of which 11.2% due to adverse events (AE). The 35 AE include: 12 cancers (incl. 7 invasive BC’s, 1 DCIS, 1 CRC), 11 cardiovascular (incl. 1 stroke, 1 AMI, 2 VTE, 1 angina, 2 TIA), 2 gynecologic (uterine polyps). Conclusions: In spite of the current negative scenario for HRT, we have reached over 1,800 women on study. Compliance is acceptable and treatment appears safe. The rate of AE is far lower than the WHI trial, possibly as a result of the different population characteristics. These preliminary findings justify the carry-on of the study in order to reach enough power for the main endpoint and perform secondary evaluations. No significant financial relationships to disclose.
Serum carboxyterminal telopeptide (ICTP) as a prognostic marker in bone metastases (BM) treated with bisphosphonates
Authors: Costa L. , Carvalho R. , Oliveira A. G. , Bicho M. , Fernandes A. , Rodrigues T. , Ali S. , Leitzel K. , Demers L. , Lipton A. 
Published: March 2020

10107 Background: Biochemical markers of bone turnover, such as N- and C-terminal cross-linking telopeptide of type I collagen have been evaluated as prognostic matkers in patients with BM. In one of such study, we found that ICTP was not affected by bisphosphonate (BP) therapy (Costa, et al., JCO 2002; 20:850–856). In this prospective study we analyzed whether the baseline level of ICTP was predictive of skeletal related events (SREs) as defined by: pathologic fractures (PF), radiation to treat BM (RT) or spinal cord compression (SCC); time to progression (TTP) and overall survival (OS) in patients with BM from solid tumors under BP therapy. Methods: We studied 116 BM patients, median age: 64 years; 67% females; 61% breast cancer; 19% prostate cancer; and 20% other tumor types. The x-ray pattern of BM was lytic in 54% patients, blastic in 23%, and mixed in 21%. At the time of study entry, all patients had serum ICTP levels measured with RIA reagents from Orion Diagnostica (reference range: 2.5–4.0 μg/L). A serum ICTP cutoff of 6.2 μg/L was established using the mean + 2D. The occurrence of SREs was recorded during the study and an objective evaluation of BM status was performed every 4–6 months. During the time period on study, patients received treatment with IV zoledronate (57%), IV pamidronate (28%), or more than one BP. The proportional hazards model was used to investigate the correlation of ICTP baseline level with time to first SRE (TTSRE), TTP, and OS; and Poisson regression with the skeletal morbidity rate (SMR): number of SREs/person/year. Results: The median follow-up was 21 months. 81.9% patients had ICTP level above 6.2 μg/L and the mean value of ICTP was 15.1 (SD 11.9) μg/L. During the time period on study, 38% had PF, 57% had RT, and 9.5% had SCC. Median TTSRE was 20 months and the SMR was 0.84. Median TTP was 12 months and median OS time was 29 months. ICTP levels above 6.2 μg/L were associated with increased mortality risk (hazard ratio (HR) 2.86, 95%CI 1.37–6.00, p=0.005) and increased SMR (incidence rate ratio 1.88, 95%CI 0.98–3.60, p=0.057), but not with TTP (HR 1.18, 95%CI 0.67–2.07, p=0,57) or TTSRE (HR 1.59, 95%CI 0.82–3.08, p=0.17). Conclusions: Elevated serum ICTP levels is associated with decreased survival and increased incidence of SREs in BM patients on BP therapy. No significant financial relationships to disclose.
Effect of HMG CoA reductase inhibitors on the grade and recurrence of colonic polyps
Authors: Surapaneni R. , Behm R. , Wood C. 
Published: March 2020

1016 Background: The burden of treating colon cancer on the healthcare system is huge and screening for colonic polyps has been very effective. Colon cancer arises from colonic polyps in a significant percent of patients and preventive measures to control colonic polyps in the form of dietary interventions, NSAIDS have been looked into. But there are no studies to our knowledge that looked at the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on colon polyps. The aim of this study was to examine the effect of HMG CoA reductase inhibitors on the grade and recurrence of colonic polyps. Methods: This retrospective case control study included review of the charts of all patients at Geisinger Medical Center who had colonoscopy and polypectomy between 1998 and 2003. These patients were divided into two groups based on the use of HMG CoA reductase inhibitors. A total of 207 patients were identified of which, 60 were in statin group and 147 were in the non-statin group. Logistic regression was used to evaluate the relationships between statin use and 1) recurrence of colonic polyps and, 2) histological grade. Additionally, Cox regression was used to examine the relationship between statin use and time until colonic polyp recurrence. Results: The rate of recurrence of colonic lesions and histological grade at follow-up were not different between the two groups. However, time until recurrence (based on time until 2nd colonoscopy) was longer in the statin group (p=0.001). This association remained after controlling for aspirin use and other characteristics of the patient (p=0.013). Conclusion: Our study suggests that HMG CoA reductase inhibitors might have a role in the secondary prevention of colonic polyps. Larger, prospective randomized studies are needed to validate this finding. [Table: see text] No significant financial relationships to disclose.
Ductal lavage (DL) of affected and unaffected breasts in women with newly diagnosed breast cancer: Can this technique be used for risk assessment?
Authors: Wood M. E. , Stanley M. , Leiman G. 
Published: March 2020

1024 Background: Ductal lavage (DL) is designed to obtain cellular material from breast ducts. The use of DL in risk assessment is under investigation. The aim of this study was to evaluate cytologic findings in DL of affected and unaffected breasts in women undergoing definitive surgery for breast cancer. Methods: Women with newly diagnosed breast cancer participated prior to surgery. Women with prior breast cancer or receiving neoadjuvant therapy were excluded. The study was IRB approved; all women gave written informed consent. Women underwent nipple aspiration followed by ductal lavage of fluid-producing ducts for both the affected and unaffected breast in the operating room prior to surgery. Cytology was interpreted as insufficient cells to make a diagnosis (ICMD), benign, mildly or markedly atypical, or malignant. Results: Twenty-three women aged 32–74 years underwent nipple aspiration of both breasts prior to definitive surgery; 1 had bilateral breast cancer. One woman had DCIS, 1 T1a, 3 T1b, 9 T1c, 6 T2, and 4 T3 lesions. Node status was N0 in 13, N1mic in 3, N1 in 5 and N2 in 3 (15 underwent sentinel node evaluation). Five women produced no NAF and therefore did not undergo DL; 18 underwent DL of at least one breast. Cytology samples were available for 30 breasts, 16 affected and 14 unaffected. Two samples contained malignant cells (one from a patient with pre-existing malignant nipple discharge), 3 moderate atypia, all from affected breasts. Benign cytology was found in 20 samples (8 affected breasts) and ICMD was classified in 5 samples (3 affected breasts). Age (</> 50), tumor size, nodal status, or sentinel node procedure were not associated with NAF production, success or cytology of DL. Conclusion: These findings suggest that DL is not effective in identifying known breast cancer. It brings into question its ability to identify women at increased risk. Future research should focus on molecular markers of risk or other means of tissue retrieval. No significant financial relationships to disclose.
Phase III trial of chemoprevention of lung carcinogenesis using green tea beverage and tea polyphenols (Polyphenon E)
Authors: Garland L. L. , Chow H. S. , Einspahr J. , Harris R. B. , Buckmeier J. , Tobar M. , Rodney S. , Hakim I. A. 
Published: March 2020

1026 Background: Oxidative reactions have been implicated as important modulators of human health and the development of disease, including cancer. Studies have shown an increased oxidant burden in chronic obstructive pulmonary disease, a disease state in which there is increased risk of lung cancer. Our overall goal is to develop a safe, feasible clinical research approach using non-invasive methods of biomarker retrieval that will serve as a model for lung cancer chemoprevention studies. The primary study objective is to determine the effects of high green tea consumption (beverage and Polyphenon E [Mitsui-Norin Co., Ltd., Shizuoka, Japan]) on biomarkers of oxidative stress that are putative modulators of lung cancer risk, including 8-hydroxydeoxyguanosine (protein oxidation), F2-isoprostanes (lipid oxidation), nitric oxide and antioxidant enzymes. Secondary objectives are to measure modulation of lung carcinogenesis-related genes in exfoliated bronchoepithelial cells. Methods: We are conducting a 6-month randomized, controlled, double-blind trial of beverage green tea or Polyphenon E capsules or a control intervention (matching double placebo) in former smokers (FS) with a ≥30 pack year smoking history and an FEV1 ≤70%. Subjects are stratified by gender and inhaler use. Changes in oxidative damage are measured in exhaled breath condensate, blood and urine. Changes in gene expression of proliferative biomarkers (EGFR, PCNA, JUN, FOS, Ki-67) and apoptosis (bcl-2, caspase 3) are being assessed in induced sputum. Results: Recruitment and screening of subjects began 6/04. As of 12/05, 559 subjects have been phone screened for eligibility; of 99 eligible subjects, 54 were excluded by spirometry. 45 subjects have been enrolled and 25 have completed the study. No significant adverse events have been reported, including no liver toxicity. We have been able to extract RNA and measure gene expression in induced sputum. Conclusion: Six-month high tea consumption in FS with at least a moderate smoking history and FEV1 ≤70% is feasible and safe. Recruitment is continuing. Supported by U01-CA-101204. No significant financial relationships to disclose.
Initiatives to improve minority participation in cancer clinical trials
Authors: Mathews K. J. , Farria D. , Springer B. C. , Randall G. 
Published: March 2020

1029 Background: Barriers to minority research participation fall into two categories with respect to research institutions: 1) Community-based factors: historical events, attitudes towards the medical system, trust in research, and referral patterns and geographic distribution of providers serving minority patients. 2) Institutional factors: system and policy issues that define where patients receive care, researcher and staff attitudes and practices, and infrastructure availability to support minority accrual. Much attention has focused on community factors but with little evidence to support specific interventions. Recent studies suggest that internal barriers may play an even more significant role. The Siteman Cancer Center’s Program for the Elimination of Cancer Disparities (PECaD) uses several internal strategies as part of its comprehensive program. Methods: First, the Siteman Cancer has raised substantial funds and changed institutional policies to improve access to cancer services for minority populations, particularly from the African-American community. Second, PECaD implemented a trial monitoring program requiring cancer investigators to set and achieve appropriate accrual based on the patient population treated in each disease area. Third, through trial monitoring and consultation with investigators, PECaD is developing core resources to help recruit and retain minority participants. Results: This approach has led to marked improvement in representative participation in cancer research. In all categories of breast research, African-American participation has climbed from 9% to 28% over five years. In nearly all disease areas, African American participation in therapeutic trials has increased steadily and in some cases exceeds the proportion of African-American patients treated in that disease area. Conclusions: Eliminating cancer disparities requires representative research participation. To achieve this goal, research institutions need to critically examine and implement changes in systems, practices and culture. Leadership, institutional commitment, and operational restructuring can result in significant change even with relatively modest financial investment. No significant financial relationships to disclose.
Correlation of statin use with breast random periareolar fine needle aspiration (RPFNA) cytomorphology in high risk postmenopausal women
Authors: Sharma P. , Kimler B. F. , Kennedy T. , Smith E. J. , Khan Q. J. , Fabian C. J. 
Published: March 2020

1031 Background: In vitro studies have demonstrated that statins (HMG CoA reductase inhibitors) suppress tumor growth and proliferation in breast cancer cell lines. Published clinical data on the chemoprotective role of statins in breast cancer are conflicting. Moreover, there are no published studies specifically examining the impact of statin use on breast cancer risk biomarkers in high risk women. We have previously demonstrated that cytologic atypia detected by RPFNA is associated with a 5 fold increase in short term risk of breast cancer in high risk women. The aim of this study was to explore the effect of statin use on breast RPFNA cytomorphology in postmenopausal women at high risk of developing breast cancer (based on personal and family history). Methods: Thehigh risk breast clinic database at the University of Kansas Medical Center was queried from April 2002 to September 2005 for statin use in postmenopausal women. We first identified postmenopausal women who underwent RPFNA while on a statin (cases). Postmenopausal women who underwent RPFNA while not on a statin (controls) were then identified and matched with statin users for known breast cancer risk factors (age, 5 year Gail risk and BMI). Frequencies of categorical variables were assessed using chi-square analysis. Continuous variables were assessed using Mann-Whitney non parametric test. Results: 504 postmenopausal women were identified. Thirty five of these 504 women underwent RPFNA while on statin therapy. For statin users (cases), the median age was 56 years, median 5 year Gail risk was 3.6%, median BMI was 28 and the median duration of statin use was 1.4 years (range 0.3 to 13 yrs). Sixty nine controls were identified. There was no difference between cases and controls with respect to HRT use (54% vs 40%, p=0.22), duration of HRT use (p=0.30) and visual breast density (p=0.80). RPFNA atypia was detected in 11% of cases and 26% of controls (p=0.13). Conclusion: Although prevalence of RPFNA atypia was less frequent among statin users, this difference was not statistically significant in this small cohort of high risk women with relatively short duration of statin use. Larger studies are warranted to investigate this further. No significant financial relationships to disclose.
UW-01: A randomized comparison of three doses of weekly docetaxel as 1st-line chemotherapy in stage IV breast cancer
Authors: Gralow J. R. , Chielens D. , Schuster G. , Storer B. , McCleod M. J. , Smith R. E. , Chowhan N. M. , Gressler V. , Miletello G. 
Published: March 2020

10522 Background: Docetaxel (DOC) is an active agent in the treatment of breast cancer. The optimal dose and dosing interval for DOC, with respect to balancing efficacy and toxicity, has yet to be determined. In this multi-center, randomized phase III trial, we attempted to compare 3 doses of single-agent weekly DOC. Methods: Patients with documented evaluable or measurable stage IV breast cancer and no prior metastatic chemotherapy were eligible. Prior adjuvant chemotherapy was permitted if ≥ 6 months had elapsed. Adjuvant exposure to DOC was allowed if ≥ 1 year prior. All patients received intravenous weekly DOC, 3 out of 4 weeks. Patients on Arm A received doses of 25 mg/m2, Arm B received 30 mg/m2, and Arm C received 35 mg/m2. The primary study outcome was time to progression (TTP). Secondary endpoints included toxicity, response rate (RR), and overall survival (OS). Targeted accrual was 600 patients. Results: The study was stopped early for feasibility reasons (poor accrual) after a total of 108 patients were enrolled at 49 U.S. sites. The median patient age was 63 years. Grade 3, 4 non-hematologic toxicity was 22%, 22%, and 23% in Arms A, B and C respectively. Nail toxicity of any grade occurred in 2 patients in Arm A, 6 patients in Arm B, and 7 patients (2 of which were grade 3) in Arm C. TTP for Arm A was 19 weeks (95% confidence intervals [CI] 10–23), 28 weeks for Arm B (95% CI 15–38), and 24 weeks for Arm C (95% CI 12–37). There was a marginally significant difference in TTP between arms A and C (HR = 1.7, 95% CI = 1.0–2.8, p = 0.05), but not between arms B and C (HR = 1.0, 95% CI 0.6–1.7, p = 0.94). RR was 26%, 27%, and 31% in Arms A, B and C, respectively. Median survival was 77 weeks for Arm A (95% CI 53–115), and 96 weeks for arm B (95% CI 53-undetermined); it has not yet been reached for Arm C. Discussion: The interpretation of study results is limited due to early stopping and resultant loss of statistical power. For the primary study endpoint, TTP, the lowest (25 mg/m2) dose may be less than optimal, but there was no observed difference between the intermediate (30 mg/m2) and highest doses (35 mg/m2) of weekly DOC. Grade 3, 4 non-hematologic toxicities were similar between the 3 arms. [Table: see text]
Expression of hormone receptors ERα, ERβ and PgR in HER2-positive breast cancers
Authors: Litwiniuk M. , Filas V. , Moczko J. , Kaleta R. , Breborowicz J. 
Published: March 2020

10525 Background: HER-2/neu gene is amplified and overexpressed in 15–20% of invasive breast cancers. HER2-positive breast cancers have a worse prognosis than HER2-negative tumors and distinctive clinical features. They express hormone receptors for estrogen (ERα) and for progesterone (PgR) less frequently than HER2-negative tumors. The identification of the other human estrogen receptor, receptor beta (ERβ), raises a question of ERβ occurrence in HER2-positive breast cancer. Patients and methods: Formalin-fixed, paraffin embedded tissues from 90 patients with invasive HER2-positive breast cancer and from 99 patients with HER2-negative breast cancer were used in this study. The HER2 status was analyzed using HercepTest TM (IHC), and IHC 2+ results were confirmed with FISH test. Immunostaining for ERα, ERβ and PgR was performed using monoclonal antibodies against ERα, PgR (DakoCytomation) and against ERβ (CHEMICON). The EnVision detection system was applied. The data were analyzed using nonparametric Fisher-Freeman-Halton test; the statistical significance was considered when p < 0.5. Results: Only 33% of the HER2-positive breast cancers were ERα-positive compared with 63% in the HER2-negative group (p < 0.001). The expression of ERβ protein was observed in almost equal frequency in both groups (57% of HER2-positive breast cancers and 57.7% of HER2-negative tumors, p = 0.889). The expression of PgR was observed in 30% of HER2-positive breast cancers and in 68.7% of HER2-negative tumors (p < 0.001). Conclusion: The expression of ERβ (unlike that of ERα and PgR) was similar in HER2-positive and in HER2-negative breast cancers. Thus, ERβ may be a potential target in future endocrine therapy for women with HER2-positive breast cancers. No significant financial relationships to disclose.