bluuebunny/crossref_metadata_2025 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.
Prognostic role of c-met tyrosine kinase receptor expression in breast carcinoma
Authors: Gisterek I. , Matkowski R. , Suder E. , Lacko A. , Ramsey D. , Szelachowska J. , Kornafel J.
Published: March 2020

10552

Background: Hepatocyte growth factor is a pleotropic growth factor that regulates cell proliferation, survival, tumor angiogenesis and metastasis. Its biological effects are mediated through interaction with its receptor: c-met protein.In this study, we evaluated c-met expression in the homogenous group of 99 patients diagnosed with stage II ductal breast carcinomas (G2, G3). We analyzed 5 and 10-years overall (OS) and disease free survival (DFS). Methods: Microscopic studies were performed on formalin-fixed, paraffin-embedded tumor tissue, obtained during surgery and stained routinely with haematoxylin and eosin. Expression of c-met was evaluated using a standard immunoperoxidase technique and percentage of cells with protein expression was counted. Survival was estimated using Kaplan-Meier method. Results: The expression of c-met was found in 37 (37.37%) tumors, with the strong expression of c-met observed only in 7 (7.07%) specimens. The 5-year DFS in patients with overexpression of c-met was statistically significantly worse (p =0.00493) compared with the group with low or no expression (recurrent rates: 57.14% vs 20.65%). Also with a time horizon of 10 years, high values of c-met expression were associated with the higher rate of recurrences (71.43% vs 30.77%, p = 0.01351). The 5-years OS rate in patients with c-met overexpression was 71.43% compared with 84.78% in the group with low or no expression, but this result did not reach statistical significance (p = 0.30345). Comparable tendency was seen in 10-years OS, which was 42.86% in patients with overexpression and 73.63% with low or no expression (p = 0.06154). Conclusions: The results of the study suggest that c-met overexpression is associated with shorter disease-free survival and it may be a useful prognostic indicator of more aggressive disease in patients with breast carcinoma.

No significant financial relationships to disclose.
Screening mammography in old women saves lives: A simulation model
Authors: Barrajon E. , Lopez A. , Adrover E.
Published: March 2020

10561

Background: Screening mammography has shown to decrease breast cancer specific death rate by 20–25% and has been recommended in women aged 40 and above, nevertheless, some country service screen programs stop screening in women older than 69, even though the sensitivity and specificity of screening mammography is highest in older women, especially those older than 80 years. The size of the older population is growing exponentially and old women have the highest incidence of breast cancer; one third of breast cancer diagnosis and half the deaths of breast cancer in USA occurred in women aged 70 and above in the year 2000. The aim of this study is to estimate the impact of mammographic screening in women aged 70 and above on breast cancer mortality. Methods: US Census, SEER, CISNET, CDC, HMD, ULTD databases were searched to obtain population data and rates of incidence and mortality of breast cancer by age. In addition, mammography screening bibliography from randomized clinical trials, meta-analysis, and service health programs publications were reviewed to estimate the impact of screening mammography on results for different strata. Analytical and simulation methods were applied for modeling the data with the aid of Mathematica to calculate breast cancer reduction rate. Results: A reduction in breast cancer mortality was observed with a magnitude proportional to age, even after taking into account competing risks of death by other causes in the aging population. Simulation of different scenarios revealed a decrease in breast cancer mortality in the range of 5 to15% for women younger than 50 years, 15 to 25% in the group of women aged 50 to 69, and 25 to 35% in women older than 69. Factors such as population life expectancy, breast cancer incidence, attrition rate in screening or cross-over, overall specificity of mammographic detection, interval of screening, impact the estimations, explaining in part some of the negative results of prevention trials. Conclusions: Reduction of breast cancer mortality by mammographic screening is proportional to age. Women aged 70 and above benefit more from mammographic screening than younger women.

No significant financial relationships to disclose.
Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC)
Authors: Green M. C. , Pusztai L. , Theriault R. L. , Adinin R. B. , Hofweber M. , Fukushima M. , Mita A. , Bindra N. , Hortobagyi G. N.
Published: March 2020

10576

Background: TAS-102 is an oral combination of 5-trifluorothymidine (FTD) and a thymidine phosphorylase (TP) inhibitor. FTD is an antineoplastic antimetabolite that causes DNA-fragmentation after passive incorporation into DNA. The TP inhibitor prevents degradation of FTD when orally administered. This agent is active against many tumor cell lines including breast cancer. In animal studies, the use of divided daily dosing of TAS-102 has resulted in increased FTD incorporation into tumor DNA. This study was conducted to determine the phase II dose and the dose limiting toxicity (DLT) of TAS-102 in pts with solid tumors/MBC. Methods: Pts with MBC refractory to standard therapy (tx) or for whom no standard tx existed were eligible to participate on study. Pts with either measurable or evaluable MBC were enrolled at an initial dose level of 80 mg/m2/day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks with standard 3+3 design. DLT was defined as any of the following in cycle 1 a. ≥ grade (gr) 3 non-hematologic toxicity (excluding nausea/vomiting); b. inability to take ≥ 75% of planned study dose per cycle; c. gr 4 granulocytopenia (GCP) lasting ≥ 3 days or febrile ≥ gr 3 GCP of any duration or gr 4 thrombocytopenia (TCP); d. > 1 week delay in administration of the next scheduled dose. Evaluation of response was conducted every 8 wks. The recommended phase II dose was defined as the highest dose level that did not cause a DLT in 1/3 or more pts in that cohort. Results: 19 pts with MBC (median age: 56; median prior tx: 4) received tx with TAS-102. A median of 2 cycles were received (range 1–24) with one pt still on study. The initial starting dose resulted in DLT in 2/3 pts. Two additional dose levels were studied. The main cycle 1 toxicities were gr 3–4 GCP in 11/19 pts; gr 4 TCP in 1/19 pt. Other grade 3–4 toxicities were rare with minimal alopecia. The recommended phase II dose was determined to be 50 mg/m2/day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks. Clinical activity was seen including prolonged disease control (> 12 weeks) in 7 pts. Conclusions: TAS-102 given BID as described is an active agent against heavily pretreated MBC with primarily hematologic toxicity.

[Table: see text]
Hepatic intra-arterial infusion (HAI) for liver metastases in pretreated metastatic breast cancer patients
Authors: Zanon C. , Airoldi M. , Pedani F.
Published: March 2020

10579

Background: Breast cancer patients (pts) with liver metastases have a poor prognosis. HAI has been frequently used for liver metastases from colorectal cancer, with better response and possibly survival than with intravenous administration. We evaluated the activity of HAI in pretreated breast cancer patients with liver metastases only. Methods: From December 2001 to October 2005 thirty patients previously treated with anthracyclines, taxanes and vinorelbine were enrolled. Median age 58 years (44–68) and median PS 1 (0–2). Eight patients (27%) had 5 or more liver nodes, seventeen (57%) had 5 to 10 metastases and five (16%) more than 10 nodes. Eighteen patients received 2 previous lines of chemotherapy (67 %), eleven 3 lines (30%) and one (3%) three lines and one cicle of high dose chemotherapy followed by ABMT. Seventeen pts received prior hormonotherapy. Two patients had been submitted to liver metastasectomy. Patients underwent percutaneous implantation of an arterial hepatic port-a-cath. HAI regimen administered on days 1–3 every 4 weeks, consisted of cisplatin 10 mg/sqm bid, mitomycin-C 1 mg/sqm bid, 5-fluorouracil 1000 mg/sqm 72 hours continuous infusion. Results: On an intent-to-treat analysis, four pts had CR (13%) with a duration of responses of 12, 18, 24 and 36 months. Fourteen pts (47%) had PR with a median duration of 7 months. Six patients had stable disease (20%) with a median duration of 3 months. Six patients (20%) had PD. Responses were more frequent in patients with PS 0 (10/13, 77%) and in patients treated with 2 previous lines of chemotherapy (13/18, 72%) than 3 or more (5/12, 42%). Median survival for the whole population was 11.8 months (5–44; 95% CI, 10.0 to 13.9). For pts with CR or PR and those who had SD, median survival was 16 months (10–44) and 10 months (8–18), respectively. No treatment-related death occurred. Grade 3–4 neutropenia in 7 % of pts. Grade 4 thrombocytopenia and grade 3 anemia 3 % of patients. Most frequent G3 non-haematologic toxicities were nausea and vomiting (3%) and alopecia (3%). We observed 2 dislodgements of catheter (7%), 3 cases (10%) of gastroduodenal ulcers, neither cases of thrombosis, nor sclerosing cholangitis. Conclusions: This intra-arterial regimen seems active in this patient population, with a very good safety profile.

No significant financial relationships to disclose.
Paclitaxel, carboplatin and trastuzumab (TCH) achieves high pathological complete remission rate after in vivo response directed 2–4 cycles of doxorubicin and cyclophosphamide (AC) in breast cancer patients
Authors: Mehta R. S. , Schubbert T. , Kong K.
Published: March 2020

10583

Background: A pathological complete remission (pCR) predicts improved survival in breast cancer (BC). Treatment with AC followed by concurrent TCH improved pCR rates to 87.5% in Her2 positive 8-patient pilot study (SABCS 2004, abs #1110), confirmed by a subsequent phase II study. We hypothesized that response adjusted AC (2–4 cycles), TCH (3–4 cycles) sequence targets topoisomerase II alpha amplified and deleted clone, respectively (SABCS 2005, abs # 5056). We report here the combined analysis of the Her2 positive (fluorescence in situ hybridization + or immunohistochemistry 3+) subset of these studies. Material and Methods: Thirty-one patients with stage IIB-IV BC were accrued. Twenty-eight of 31 patients received AC in a dose dense manner with GM-CSF support. Patients received carboplatin calculated at AUC of 2 and paclitaxel at 80 mg/m2 for 3 weeks followed by 1 week of rest (1 cycle) for a maximum of 4 cycles. Concurrent trastuzumab 4 mg/kg loading dose, then 2 mg/kg/wk was administered for 12–16 weeks. Results: Twenty-nine of 31(94%, CI, 0.79–1) patients showed a clinical complete or partial response (cCR, or cPR). Nineteen of 27 patients (70%, CI, 0.50–0.86) achieved a pCR at surgery; two additional patients had ≤3 mm residual invasive cancer; and lymph node negativity rate was 73%. Of the 3 additional patients with cCR, 1died (underlying cirrhosis), 1 refused surgery, and 1 awaits surgery. A fourth patient with cPR awaits surgery. Ninety percent of the patients (28/31, CI, 0.74–0.98) are alive, and 77% (24/31, CI, 0.59–0. 90) are progression free at median follow up of 19 months (range 6–35 months). Median ejection fraction by echocardiogram was 60% (range 50–74); no patient had clinical cardiac dysfunction. One patient each on GM-CSF and peg-GCSF developed neutropenic fever. Conclusion: Short course of TCH following response adjusted 2–4 cycles of AC will have an improved therapeutic ratio with minimum cardiac toxicity and maximal response.

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Quality assurance in surgical trials of new techniques
Authors: Mansel R. E. , McNeill F.
Published: March 2020

10584

Most surgical trials include quality assurance for data and documentation, but the variable of surgical performance is often ignored, even when new techniques form one arm of the trial. Recent trials of sentinel node biopsy (NSABP-B32, ALMANAC, and AMAROS) have have attempted to control this variable by pre randomisation audit of surgical performance, but logistics and cost have limited this approach. The B-32 and ALMANAC trials did show that defined and validated pre trial audits produced high rates for localisation of the sentinel node (>95%) and false negative rates of <10%. However these results from motivated trial surgeons/teams may not be reproduced when the techniques are rolled out for general use. In the UK participation in the NEW START national training programme has been endorsed by the Health Department as evidence of satisfactory training in sentinel node biopsy. Surgeons and their teams attend a standardised theory session backed up with detailed training material on DVD. Then a training team visits with the surgical team and supervises the first 5 procedures performed by the surgeon in his own OR, after which a further 25 procedures with completion ALND are performed. All these data are evaluated prospectively centrally. A performance standard of >90% localisation rate and <10% false negative was set prospectively to determine if the surgeon is eligible for certification. The programme is currently achieving 98% localisation and <5% false negative rates in surgeons who have never performed the procedure previously, and 50% of breast surgeons in England have attended the theoretical module of the training. These data suggest that surgical trials involving new techniques should be preceeded by training and individual surgeon audit prior to randomising patients. Abbreviations OR = Operating Room ALND = Axillary Lymph Node Dissection.

No significant financial relationships to disclose.
Optimal tolerance of an all-oral combination chemotherapy (CT) of oral vinorelbine (NVBo), capecitabine (C) with/without trastuzumab (T) in metastatic breast cancer (MBC) patients (pts): Safety Results of two international multicenter studies
Authors: Chan A. , Tubiana N. , Ganju V. , Conte P. , Bougnoux P. , Aubert D. , Bourlard T. , Becquart D.
Published: March 2020

10607

Background: Combination therapy of T and Vinorelbine has recently been reported to be an active and safe regimen for HER2 positive MBC pts. The current safety analysis investigated NBVo and C, which offers the convenience of an all-oral regimen given alone or in combination with T, if pts were HER2 positive, as first-line therapy for MBC patients, KPS ≥ 70%. Methods: In the HER2 negative study ([A]) (IHC 0- 2+/FISH−) 38 pts received: NVBo 60 mg/m2 (Cycle 1) or 80 mg/m2 (from Cycle 2) D1 & D8 and C 2000 (1500 if ≥ 65 y) mg/m2/d D1-D14 every 3 weeks. In the HER2 positive study ([B]) (IHC 2+ or 3+ confirmed by FISH+) 25 pts received : NVBo, and C at the same doses as [A] + T, 4 mg/kg on D 1 as loading dose and then 2 mg/kg i.v. weekly starting on D8. Treatment was continued in both studies till progression. Results: Median age: [A] 61.5y (17 pts ≥ 65 y), [B] 53.0 y (5 pts ≥ 65 y); Prior (neo)adjuvant CT: [A] 21 pts (55.3%), [B] 16 pts (64%); Visceral involvement: [A] 28 pts (73.7%), [B] 22 pts (88%); > 2 metastases: [A] 15 pts (39.5%), [B] 10 pts (40%); Median dose intensity (%): NVBo [A] 45.1 mg/m2/w (90.5%), [B] 39.5 mg/m2/w (75.7%); C [A] 7733 mg/m2/w (87%), [B] 7140 mg/m2/w (83.7%); T [B] 2.1 mg/kg/w (98.1%). NVBo dose escalation to 80 mg/ m2: [A] 33 pts (94.3%), [B] 23 pts (92%). Tolerance: ([A] n = 38 pts, [B] n = 25 pts) (% of pts with G3/4 NCI CTC v2): Neutropenia [A] 29/16, [B] 52/16; Infection with G3/4 neutropenia [A] 3/3, [B] 8/0; Stomatitis [A] 5/3, [B] 0/4; Bilirubin [A] 3/0, [B] 0/0; HF Syndrome [A] 3/0, [B] 8/0; Nausea [A] 3/0, [B] 0/4; Vomiting [A] 10/0, [B] 4/4; Diarrhoea [A] 5/0, [B] 12/4; Ileus [A] 0/0, [B] 4/0; Febrile Neutropenia: [A] 5%, [B] 8%. Efficacy: the preliminary results on the evaluable pts confirm an optimal disease control (CR + PR + SD): [A] 25/27 pts (92.6%), [B] 22/24 pts (91.7%). Conclusion: The combination of NVBo and C can be safely administered in the palliative setting of MBC and calls for further comparative studies vs i.v. combinations. The addition of T in HER2 positive patients does not alter the favourable safety profile.

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Usage trends of minimally absorbed vaginal estrogens in breast cancer patients versus patients with non-breast malignancies
Authors: Castiel M. , Masakhalia S. , Krychman M. , Stier B. , Amsterdam A. , Gemignani M. , Kauff N.
Published: March 2020

10620

Background: To determine if differences exist in the use of minimally absorbed vaginal estrogens in a breast cancer population versus one with non-breast malignancies. Methods: A retrospective review of all patients with documented malignancy who were prescribed vaginal 17-β-estradiol tablets (Vagifem, Novo-Disc, Princeton, New Jersey) through the General Gynecology Service from July 1, 2003 to June 30, 2004. Data were accessed from the pharmacy health information computerized system. All patients complained of dyspareunia, and examination was consistent with vaginal atrophy. Comparison between groups was performed using the Fisher Exact Test and t-test. Results: 152 patients were identified_81 patients with breast cancer diagnoses and 71 with non-breast malignancies. There was no difference in the mean age of patients in either group, 56.9 vs. 55.1 years. (p = 0.30). Overall, 60 of the 152 patients refilled their prescriptions through the time of last follow-up. There was no difference in the proportion of breast versus non-breast cancer patients who continued vaginal estradiol, 39.5% (32/81) versus 39.4% (28/71) respectively. When the cohorts were stratified by age ≤ 50 or >50 at the time of initial consultation, 79% (11/14) of breast cancer patients age ≤ 50 years refilled their prescriptions at follow-up compared to 31.3% (21/67) of patients >50 (p = 0.002). In women with non-breast malignancies there was no age-related difference in the proportion who obtained refills: 35% (7/20) ≤ 50 years versus 41.2 % (21/51) >50 years (p = 0.79). Conclusions: Minimally absorbed vaginal estrogens appear to be viewed favorably amongst the younger breast cancer patient population. The older breast cancer population does not appear to continue vaginal estradiol use long-term. This may be due to differences in relationship status, interval from menopause to diagnosis, prior exposure to estrogen, or relief of symptoms with alternative therapies. These findings are different than those observed for similar patients with non-breast malignancies. Further studies looking at the use of minimally absorbed vaginal estrogens are needed to further evaluate the usage trends in differing patient populations.

No significant financial relationships to disclose.
Expression of critical genes used as prognostic biomarkers and DNA damage in lymphocytes from breast cancer patients
Authors: Franke F. , Agnoletto M. , Saffi J. , Guecheva T.
Published: March 2020

10641

Breast cancer is the most common malignancy among women and its rate of mortality is still high. The increase knowledge of breast cancer biology is heaving great impact on determining the clinical prognosis and response to treatment. Impaired DNA repair may elevate the risk of malignant transformation of breast cells due to the accumulation of spontaneous mutations in target genes and increasing susceptibility to exogenous carcinogens. The present study was designed to evaluate the relationship between DNA damage and expression of some critical genes including TP53, c-ERBB2, ER (Estrogen Receptor) and PR (Progesterone Receptor) in breast cancer. Blood samples were obtained from female patients with diagnosed breast cancer before chemotherapy as well as from healthy individuals, and were processed in 24 hours. To evaluate the role of DNA repair in breast cancer we determined the level of DNA damage and the capacity to remove DNA damage induced by hydrogen peroxide in the peripheral blood lymphocytes. For this purpose the alkaline version of the comet assay, which provides a sensitive tool to investigate DNA damage and repair, was applied. The level of basal DNA damage was higher in breast cancer patients compared to the control group. Considerable inter-individual variations of DNA damage and repair in breast cancer patients were observed both before and after the treatment. The correlation between DNA damage in peripheral blood and expression of p53, c-erbB-2, PR and ER was analyzed. This preliminary study indicates that the DNA damage accumulation, observed in peripheral blood lymphocytes of breast cancer patients in early stages, could be attributed to impaired DNA repair. Our results suggest that DNA damage, as evaluated by the comet assay, seems to be useful molecular biomarker for monitoring ongoing exposures to DNA damaging agents. Such a research on the mutagen sensitivity and efficacy of DNA repair could impact on the development of new diagnostic and screening strategies. Work Supported by FAPERGS and GENOTOX (UFRGS).

No significant financial relationships to disclose.
Benefits of zoledronic acid compared with placebo in breast cancer patients with bone metastases based on analysis of pain, analgesic use, and performance status
Authors: Aogi K. , Kohno N. , Minami H. , Takashima S.
Published: March 2020

10653

Background: We previously reported that zoledronic acid significantly reduced skeletal complications by 39% compared with placebo in breast cancer (BC) patients with bone metastases in a multicenter randomized trial conducted in Japan. To assess the effect of zoledronic acid in the maintenance of patient’s mobility or autonomy, we conducted a retrospective analysis of pain, analgesic use, and performance status (PS) among patients of this trial. Methods: 228 women with bone metastases were randomized to 4 mg zoledronic acid (n = 114) or placebo (n = 114) every 4 weeks for 1 year. At baseline and every 4 weeks during treatment, pain scores were assessed using the Brief Pain Inventory (BPI) on a scale of 0 to 10, and analgesic use was scored on a 4-point scale from none (0) to strong narcotics such as morphine (4). Eastern Cooperative Oncology Group (ECOG) PS was assessed at baseline and at study end. Results: Unlike patients receiving placebo who’s pain scores increased, patients treated with zoledronic acid had a significant decrease from baseline BPI composite pain score from week 4 to week 52: mean decrease of 0.86 in the zoledronic acid group at week 52 versus a mean increase of 0.62 in the placebo group; P < .05. Patients treated with zoledronic acid had very little change in analgesic scores, whereas patients in the placebo group had a mean increase in analgesic score (approximately 0.5) by study end. Shift table analysis of ECOG PS showed that 61% of patients in the zoledronic acid group had no change in PS, and 28% had worsening of ECOG PS of at least 1 grade from baseline to study end. In comparison, 54% of patients in the placebo group had no change in PS, and 36% had worsening of PS. Approximately 10% of patients in both treatment groups had an improvement in PS. Conclusions: This analysis shows that treatment with zoledronic acid reduced pain and prevented a worsening of ECOG PS in a larger percentage of patients compared with placebo, consistent with the demonstrated reduction in the rate of skeletal complications. This suggests that zoledronic acid may improve quality of life and maintain autonomy and mobility in breast cancer patients with bone metastases.

No significant financial relationships to disclose.